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Macrophages in rheumatoid arthritis

Arthritis Research & Therapy volume 2, Article number: 189 (2000) Cite this article

Abstract

The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains an efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage.

Introduction

Macrophages appear to play a pivotal role in RA because they are numerous in the inflamed synovial membrane and at the cartilage-pannus junction. They show clear signs of activation, such as overexpression of major histocompatibility complex class II molecules, proinflammatory or regulatory cytokines and growth factors [eg IL-1, IL-6, IL-10, IL-13, IL-15, IL-18, tumour necrosis factor (TNF)-α and granulocyte-macrophage colony-stimulating factor (GM-CSF)], chemokines and chemoattractants [eg IL-8, macrophage inflammatory protein (MIP)-1 and monocyte chemoattractant protein (MCP)-1], metalloproteinases and neopterin [1,2,3,4]. It is unlikely that macrophages occupy a causal position in the pathogenesis of RA (except for their function as antigen-presenting cells in the hypothesis of a primary autoimmune disorder) [5]. However, these cells of the innate immune system possess broad proinflammatory, destructive and remodelling capacities, and considerably contribute to inflammation and joint destruction both in the acute and chronic phases of RA. Also, activation of the monocytic lineage is not restricted to synovial macrophages, but extends to circulating monocytes and other cells of the mononuclear phagocyte system, including precursors of the myelomonocytic lineage in the bone marrow [2,3,6].

Thus, even before the cause of RA is identified [whether it is an infectious cause, or a clearly defined (auto)antigen or a genetic alteration (or several)], several facts render monocytes/macrophages attractive therapeutic targets. The first is the correlation between radiological progression of joint destruction and degree of synovial macrophage infiltration [7]. Second, the coincidence of therapeutic efficacy of conventional antirheumatic therapy with downregulation of functions of the mononuclear phagocyte system [8,9] is in accord with the increasing knowledge of macrophage-specific effects of such drugs [10]. Third, the efficacy of biological therapies directed at cytokines produced predominantly by macrophages has been demonstrated [11,12]. Fourth, conventional or experimental drugs can be targeted at macrophages, including their subcellular compartments [2]. The final factor in support of targeting monocytes/macrophages for treatment of RA is the differential activation of intracellular signal transduction pathways that underlie different macrophage effector functions, in conjunction with the availability of more specific inhibitors of key metabolic enzymes and/or particular signal transduction pathways [13,14,15].

Differentiation of the mononuclear phagocyte system in rheumatoid arthritis

Cells of the myelomonocytic lineage differentiate into several cell types that are involved in disease (ie monocytes/macrophages, osteoclasts and dendritic cells). As a result of their marked plasticity, these differentiation pathways can be influenced by particular pathophysiological stimuli (eg an excess/imbalance of cytokines or growth factors), resulting in altered differentiation or maturation if regulatory mechanisms fail. In RA, such alterations have been already described at several levels (ie in inflamed joints, peripheral blood and bone marrow).

In the RA synovial membrane, a first differentiation step is that from recently immigrated monocytes to mature macrophages [16]. These subsets differentially colonise the synovial sublining and lining layer, respectively, as well as the superficial and deep layers of the lining [7]. A possible functional diversity in these areas, which is emphasized by the expression of different activation markers and adhesion molecules [17], may differentially contribute to disease progression [7].

Locally, synovial macrophages also differentiate into stimulatory or inhibitory subpopulations, which are known to influence T-cell reactivity differentially [18]. In experimental arthritis, for example, immunoregulatory macrophages greatly affect T-cell responses to arthritogenic proteins [19] and, upon nonselective targeting, influence clinical and histopathological improvement in arthritis [20]. In RA, macrophage subpopulations may be responsible for the separate synthesis of proinflammatory (eg IL-1 and TNF-α) or regulatory cytokines (eg IL-10), the balance of which is critical to perpetuation of disease [21,22]. A subset of synovial macrophages may also exert a predominant role in angiogenetic processes [23].

In the RA synovial fluid, a subset of mononuclear cells presents with a double phenotype of activated T cells and macrophage-like cells [24]. Whether this promiscuity is related to plasticity of common precursors, or is the epiphenomenon of a central differentiation defect remains to be clarified.

Alterations in the macrophage lineage are also evident in extrasynovial compartments. In the bone marrow, RA patients with active or severe disease display faster generation of CD14+ myelomonocytic cells and faster differentiation into human leucocyte antigen (HLA)-DR+ cells than do control individuals [25]. Myeloid precursors are also elevated in the bone marrow adjacent to rheumatoid joints, in correlation with the local levels of IL-1 [26]. A common potential trigger for these bone marrow alterations may be the altered monokine (eg IL-1, IL-6, TNF-α) or growth factor milieu (eg GM-CSF), which builds up in the circulation [6,8], and in the bone marrow [27] of RA patients. On the other hand, the in vitro differentiation of bone marrow precursor cells becomes insensitive to GM-CSF [25], suggesting intrinsic alterations in the myelomonocytic lineage.

Possible bone marrow anomalies may also underlie the presence of highly proliferative potential colony-forming cells in the peripheral blood of RA patients with severe disease and high incidence of interstitial pulmonary involvement [28,29], a factor of poor prognosis in RA. Finally, bone marrow stromal cells also overexpress bone marrow stromal antigen (BST)-1, a pre-B-cell growth factor that is significantly elevated in the sera of patients with severe RA [30], with growth inhibition effects on monocytes/macrophages. These observations, as well as that of the existence of a macrophage activation syndrome in severe cases of systemic juvenile RA [31], suggest that the spectrum of arthritis severity may be associated with the degree of systemic activation of monocytes/macrophages. This is also supported by the extra-articular terminal differentiation of macrophages within rheumatoid nodules, the latter a sign of clinical severity [32,33].

The involvement of the myelopoietic system in RA may also partly explain the mode of action of slow-acting antirheumatic drugs, possibly targeting altered precursors [34], or that of stem-cell transplantation therapy [35].

Activation of the mononuclear phagocyte system in rheumatoid arthritis

Synovial compartments

Synovial membrane

In the RA synovial membrane, a surface layer of HLA-DR+, CD14+ and CD68+ macrophages is typically followed by a layer of fibroblasts [2]. Below the lining layer, macrophages are distributed in lymphoid aggregates or in diffuse infiltrates, in the former case adjacent to activated CD4+ lymphoid cells and in the latter case near CD8+ T cells [36], suggesting active participation in possible (auto)immune processes. In addition, macrophages are located close to synovial fibroblast-like cells that display a typical morphology, which are believed to be centrally involved in tissue destruction.

The degree of macrophage infiltration/activation correlates not only with the joint pain and general inflammatory status of the patient [37], but also with the radiological progression of permanent joint damage [7], the disease feature that ultimately determines quality of life.

In chronic RA, the prevalence of certain histological configurations may represent an important variable for the clinical course. High TNF-α and IL-1β production, for example, may be associated with granulomatous synovitis, a rare condition that is more frequently associated with subcutaneous rheumatoid nodules [32]. Conversely, these cytokines appear to be modestly elevated in diffuse synovitis, which may be associated with seronegative RA [32]. These features may also explain some variability among studies on the abundance of TNF-α and/or TNF-α receptor expression in the RA synovial membrane [38,39], and, possibly, the variable sensitivity to anti-TNF-α therapy [11].

Myeloid-related dendritic cells are also enriched in RA synovial compartments. Their efficacy as antigen-presenting cells and their interdigitating location in perivascular lymphoid aggregates are optimal prerequisites for the presentation of putative arthritogenic antigens to T cells and for the regulation of B cells [40].

Cartilage-pannus and bone-pannus junction

At the site of tissue destruction, macrophages express significant amounts of the inflammatory cytokines IL-1, TNF-α and GM-CSF [2] and contribute to the production of the proteases collagenase, stromelysin, gelatinase B and leucocyte elastase [41]. Although gelatinase B levels positively correlate with disease progression and severity [42], the potential of macrophages to degrade cartilage matrix components directly may be modest [41], assigning macrophages the position of amplifyers of the pathogenetic cascade (especially via activation of fibroblasts) rather than primary effectors of tissue destruction. The situation may be quite different at the bone-pannus junction, where osteoclasts derived from the myelomonocytic lineage strongly contribute to bone erosion [43], possibly under the influence of local cell-cell contact and abundant cytokines.

Peripheral blood

The activation of circulating monocytes in RA, although unclear in its extent [44], is evidenced by the following: spontaneous production of prostanoids and prostaglandin E2 [45], cytokines [8,46,47], soluble CD14 [2] and neopterin [8], the latter a molecule exclusively produced by human mononuclear phagocytes in correlation with disease activity [48]; increased production of the matrix-degrading enzyme gelatinase B [42,49] and the metalloprotease inhibitor tissue inhibitor of metalloproteinase (TIMP)-1 [50]; expression of manganese superoxide dismutase, a critical enzyme for the control of oxygen radicals [50]; increased phagocytic activity [51]; increased integrin expression and monocyte adhesiveness [47,52]; presence of activated suppressor monocytes [18,53]; and, more generally, gene activation with a pattern closely resembling the synovial activation pattern.

Differential analysis of gene patterns in RA monocytes collected upon initial and final therapeutic leukapheresis [6] (a procedure that induces clinical remission in severe RA, presumably by reducing the degree of monocyte activation) [8,54] has recently shed light on gene expression at different stages of monocyte activation. In addition to the expected cytokines (IL-1α, IL-1β, IL-6, TNF-α), gene activation in the florid stage of disease has also been documented for growth-related oncogene protein (GRO)-α/melanoma growth-stimulatory activity, MIP-2/GRO-β, ferritin, α1-antitrypsin, lysozyme, transaldolase, Epstein-Barr virus encoded small nuclear RNA (EBER)-1/EBER-2-associated protein, thrombospondin-1, an angiotensin receptor-II carboxyl-terminal homologue, the RNA polymerase-II elongation factor, and for five unknown/functionally undefined genes [6]. Because a number of these molecules (IL-1α, IL-1β, IL-6, TNF-α, GRO-α, ferritin, lysozyme and thrombospondin-1) are also (over)expressed in RA joints [6], monocytes appear to be preshaped in a 'rheumatoid' phenotype before their entry into the inflamed synovial tissue. This is further supported by overexpression of the human cartilage glycoprotein gp39 [55], a late macrophage differentiation marker [56], in circulating monocytes and tissue macrophages. The findings regarding novel or functionally undefined genes also indicate that the extent of systemic monocyte/macrophage activation remains to be fully explored.

Stimulation/regulation of monocyte/macrophage activation in rheumatoid arthritis

Cell-cell interaction

A significant part of macrophage effector responses occurs in the absence of soluble stimuli, through cell contact-dependent signalling with several inflammatory cells [57,58].

T cell-macrophage interaction

Accessory, inflammatory, effector and inhibitory macrophage functions can be stimulated by paraformaldehyde-fixed T cells or plasma membranes of T cells [57], provided that these are preactivated and express the surface molecules that are involved in such stimulation (eg CD69) [57]. In response to such interaction, monocytes produce metalloproteinases, IL-1α and IL-1β [59,60]. Also, T cells that are prestimulated in an antigen-mimicking manner stimulate TNF-α and IL-10 production, once they are in contact with monocytes [61]. Conversely, fixed T cells stimulated in an antigen-independent manner (ie with IL-15, IL-2, or a combination of IL-6 and TNF-α) induce monocyte production of TNF-α, but not IL-10 [62]. These findings have resulted in the hypothesis that early RA reflects antigen-specific T cell-macrophage interactions. Conversely, chronic RA may be associated with antigen-independent interactions, which are dominated by an exuberant cytokine milieu. This model would also explain the relative paucity of IL-10 in the RA synovial membrane (see below).

Fibroblast-macrophage interaction

Because macrophages and fibroblasts appear to be the most active cells in the RA synovium, their interaction is particularly interesting in view of the resulting inflammation and tissue damage. Indeed, the mere contact of these cells elicits the production of IL-6, GM-CSF and IL-8 [63]. The cytokine output can be enhanced or downregulated not only by addition of proinflammatory or regulatory cytokines (eg IL-4, IL-10, IL-13 or IL-1 receptor antagonist), but also by neutralization of the CD14 molecule [63]. Also, in vitro model systems show significant cartilage degradation by cocultures of mouse fibroblasts and macrophages, a response markedly exceeding that observed with each culture alone [64]. More recent studies [65] have shown that purified human synovial fibroblasts cocultured with myelomonocytic cell lines induce cartilage degradation in vitro. The mechanism of this response, however, seems to be paracrine- and not cell contact-mediated, because cartilage degradation is most effectively blocked by a mixture of anti-IL-1 and anti-TNF-α monoclonal antibodies.

Soluble stimuli

Proinflammatory cytokines

IL-15, an IL-2-like cytokine with chemoattractant properties for memory T cells, is highly augmented in RA synovial fluid, being produced by lining layer cells, including macrophages [66]. Notably, IL-15-stimulated peripheral blood or synovial T cells induce macrophages to produce IL-1β, TNF-α, IL-8 and MCP-1 [62,67,68], but not IL-10 [61]. Because IL-15 is also produced by macrophages themselves, this cytokine may (re)stimulate T cells, possibly contributing to a self-perpetuating proinflammatory loop [67].

The lymphokine IL-17, which is produced in approximately 90% of RA synovial explant cultures, but only in 16% of osteoarthritis cultures, strongly stimulates macrophages to produce IL-1 and TNF-α [69]. The induction of TNF-α production can be completely reversed by addition of IL-10 [69]. IL-17, which is present in T cell-rich areas of RA synovial samples, is exclusively produced by T-helper (Th)0 or Th1 clones that are derived from the synovial membrane or synovial fluid of RA patients [70]. In addition, IL-17 indirectly induces the formation of osteoclasts from progenitor cells [71] and enhances the production of nitric oxide (NO) in articular chondrocytes [72], thus potentially contributing to cartilage and bone destruction.

In the RA synovial membrane IL-18, a cytokine of the IL-1 family [73], is expressed most prominently in CD68+ macrophages that are contained in lymphoid aggregates [4]. CD14+ macrophages of the RA synovial fluid also express the IL-18 receptor [4]. IL-18, either alone or in concert with IL-12 and IL-15, strongly enhances the production of IFN-γ, TNF-α, GM-CSF and NO by cultured synovial cells. Treatment with recombinant murine IL-18 markedly aggravates experimental arthritis [4], indicating that IL-18 has proinflammatory effects in this disorder.

Bacterial/viral components

The ability of bacterial toxins or superantigens to initiate proinflammatory responses that are characterized by secretion of macrophage-derived cytokines is relevant in view of the possible micro-organism aetiology of RA. Lipopolysaccharide, for example, binds to macrophages through the CD14 receptor and, in vitro, stimulates the production of IL-1β, TNF-α and MIP-1α [74]. Staphylococcal enterotoxin B, also a potent macrophage-activating factor in vitro and in vivo, enhances arthritis in MRL-lpr/lpr mice. In this case, anti-TNF-α therapy reverses both the severe wasting effects of staphylococcal enterotoxin B and the incidence of arthritis, indicating that TNF-α is central in this system [75]. Lipoarabinomannan, a mycobacterial lipoglycan that is involved in attenuating host immune responses and entry of mycobacteria into macrophages [76], induces monocyte chemotaxis, as well as selective production of IL-12 and subsequent differentiation of T cells toward a Th1-like phenotype [77,78]. It also stimulates macrophages to produce TNF-α, GM-CSF, IL-1, IL-6, IL-8 and IL-10 [76].

More generally, the prolonged persistence of obligate or facultative intracellular pathogens in macrophages may directly lead to the development of arthritis. This is the case with the Ross River virus, which causes human epidemic polyarthritis [79], or with the caprine-arthritis encephalitis lentivirus, which causes a disorder in which viral replication within macrophages correlates with the severity of tissue pathology [80]. Further interesting cases are arthritis associated with human immunodeficiency virus-1 infection, which, as with all other manifestations of this disease, is due to virus tropism for macrophages [81], and that associated with human parvovirus B19 [82].

Hormones

RA undergoes clinical fluctuations during the menstrual cycle and during pregnancy. These observations have a pathophysiological basis in the expression of sex hormone receptors on RA synovial macrophages [83]. Indeed, physiological concentrations of oestrogens stimulate the production of the proinflammatory cytokine IL-1 by RA macrophages. Conversely, higher oestrogen concentrations inhibit IL-1 production, perhaps mimicking the clinical improvement that occurs during pregnancy [83]. Thyroid or other neuroendocrine hormones can also influence RA, at least partly through actions on macrophages [84,85].

Regulation of monocyte/macrophage activation in rheumatoid arthritis

Regulatory cytokines

The anti-inflammatory cytokine IL-4 is believed to play a protective role in arthritis, although its virtual absence from synovial samples points to the lack of protective mechanisms, rather than to active regulation [86]. This Th2-like cytokine downregulates monocyte/macrophage cytotoxicity and cytokine production [87], including that of TNF-α and TNF-α receptors [88], as well as IL-15-induced chemokine production [68]. Notably, IL-4 decreases IL-1β production while increasing IL-1 receptor antgonist production, thus suggesting a 'coordinated' anti-inflammatory approach [89]. IL-4 also decreases the mRNA production of cyclo-oxygenase 2 and cytosolic phospholipase A2, thereby reducing the levels of prostaglandin E2 [90,91]. In RA, IL-4 decreases monokine production in ex vivo synovial specimens [86], or TNF-α receptor expression by synovial fluid macrophages [88]. Importantly, IL-4 reduces bone resorption [86] as well as synovial proliferation in vitro [22]. Consistently, experimental therapy with IL-4 clearly suppresses streptococcal cell wall-induced arthritis, a strongly macrophage-dependent model [89]. In considering a combined antimacrophage and immuno-therapeutic approach in autoimmunity, IL-4 should be the elective molecule because of its ability to regulate macrophages and to shift the cytokine pattern from a Th1-like to a Th2-like predominance [92]; however, induction of fibrosis may limit its therapeutic applicability.

IL-10 is a macrophage-derived cytokine with clear autocrine functions [93]. Accordingly, IL-10 reduces HLA-DR expression and antigen presentation in monocytes [87] and inhibits the production of proinflammatory cytokines, GM-CSF and Fcγ receptors by synovial macrophages [87]. Consistently with cytokine and chemokine downregulation, IL-10 clearly suppresses experimental arthritis [94].

In spite of IL-10 elevation in serum and synovial compartments of RA patients [61,87], some studies [95] have suggested a relative deficiency in IL-10. A combined IL-4/IL-10 deficiency may therefore shift the cytokine balance to a proinflammatory predominance. Because of the autocrine effects of IL-10 [93], this may further enhance the 'rheumatoid' macrophage imprint. Although recombinant IL-10 appears to be an optimal candidate for treatment of RA [96], the induction of soluble and membrane TNF-α receptors on monocytes and synovial fluid macrophages [88], as well as the lack of efficacy in some cohorts of RA patients [97], currently question the broad applicability of this treatment.

IL-11 is present in synovial membrane, synovial fluid and sera of RA patients, and blockade of endogenous IL-11 increases endogenous TNF-α production in RA synovium in vitro [98], whereas recombinant human IL-11 reduces the production of TNF-α and IL-12 from activated macrophages [99]. IL-11 may represent another example of a paracrine regulatory loop, because IL-1α and TNF-α synergistically stimulate the production of IL-11 in rheumatoid synovial fibroblasts [100]. Treatment with IL-11 decreases clinical severity and prevents joint damage in murine collagen-induced arthritis [101], which is in accord with high levels of IL-11 mRNA in clinically uninvolved paws [102]. Clinical studies with recombinant human IL-11 have been initiated in several inflammatory conditions, including RA [103].

Similarly to IL-4 and IL-10, IL-13 exerts suppressive effects in experimental arthritis, probably through a selective effect on monocytes/macrophages [104]. In RA, IL-13 is produced by synovial fluid mononuclear cells, which, when exposed to exogenous IL-13, diminish their own production of IL-1 and TNF-α [105].

The question regarding whether IL-16 is proinflammatory or anti-inflammatory is still under debate [106]. In the RA synovial membrane, IL-16 is present in CD68- synovial fibroblasts [107] and CD8+ T cells [108]. In a human synovium/severe combined immunodeficiency mouse chimera, IL-16 behaves as an anti-inflammatory cytokine by strongly reducing levels of mRNA for IFN-γ, IL-1 β and TNF-α [but not for transforming growth factor (TGF)-β], and by decreasing the numbers of cells that express IFN-γ and TNF-α in the human implant [108]. IL-16 therefore appears to be yet another potential candidate for RA treatment, but one that requires care in view of its strong T-cell chemoattractant features.

Monocyte/macrophage effector molecules in rheumatoid arthritis

Proinflammatory cytokines

Tumour necrosis factor-α

TNF-α is a pleiotropic cytokine that increases the expression of cytokines, adhesion molecules, prostaglandin E2, collagenase and collagen by synovial cells [109]. In RA, TNF-α is mostly produced by macrophages in the synovial membrane and at the cartilage-pannus junction [38] and is believed to be a proximal cytokine in the inflammatory cascade. While, on average, approximately 5% of synovial cells express TNF-α mRNA in situ [110], the degree of TNF-α expression in the synovial tissue appears to depend on the prevailing histological configuration [32].

The importance of TNF-α is evidenced by several experimental and clinical observations: lymph node TNF-α production precedes clinical synovitis in experimental arthritides [111,112]; neutralization of TNF-α suppresses collagen-induced arthritis and reduces inflammation in human/murine severe combined immunodeficiency arthritis [38,113]; TNF-α, in combination with IL-1, is a potent inducer of synovitis [114]; transgenic, deregulated expression of TNF-α causes development of chronic arthritis [115]; the TNF-α levels in the synovial fluid correlate with the number of lining macrophages and with the degree of radiologically assessed bone erosion [116]; and serum TNF-α and soluble TNF receptors 1 and 2 are increased in active, systemic juvenile rheumatoid arthritis, including some cases of macrophage activation syndrome [31].

TNF-α exists as a membrane-bound and a soluble form. Transmembrane TNF-α appears to be involved in local, cell contact-mediated processes, and appears the prime stimulator of the R75 receptor [117]. Interestingly, the transgenic expression of this form alone is sufficient to induce chronic arthritis [118]; likewise, a mutant membrane TNF-α, which utilizes both R55 and R75 receptors, can also cause arthritis [119]. Conversely, the soluble form of TNF-α, shed via metalloprotease cleavage from the membrane-bound form [120], primarily stimulates the R55 receptor, acting transiently and at a distance [117].

Tumour necrosis factor-α receptors

TNF-α receptors are found in synovial tissue and fluid of RA patients [38,39,121], especially in severe disease [121]. There are two known TNF-α receptors: R55 (TNF-α receptor 1; high-affinity receptor) and R75 (TNF-α receptor 2; low-affinity receptor). The resulting stable R55 or transient R75 character of the ligand-receptor complex mediates different cellular responses to soluble and transmembrane TNF-α [122]. In general, TNF-α receptors can operate independently of one another, cooperatively, or by 'passing' TNF-α to one another [117]. This complexity may explain the tremendous sensitivity of target cells to minute concentrations of TNF-α, as well as the considerable variety of its effects. TNF-α receptors can also be shed, binding to soluble TNF-α and hence acting as natural inhibitors in disease [123].

Consistent with the pivotal role of TNF-α in arthritis [124], clinical trials with intravenous administration of chimaeric anti-TNF-α monoclonal antibodies or TNF-α receptor constructs have shown remarkable efficacy in acute disease [11], with long-term safety [125] and slowing-down of radiological disease progression [126,127].

Also, in accordance with the activating role of TNF-α in leucocyte extravasation [128], anti-TNF-α treatment reduces endothelial E-selectin and vascular cell adhesion molecule-1 in synovial samples, as well as the levels of E-selectin, intercellular adhesion molecule-1, IL-8 and vascular endothelial growth factor in the circulation [129]. This downregulation may lead to deactivation of the vascular endothelium and suppression of angiogenesis, as substantiated in animal studies [129].

Interleukin 1

In RA, IL-1 gene expression is found predominantly in CD14+ macrophages [130], and IL-1 levels in the synovial fluid significantly correlate with joint inflammatory activity [21]. This cytokine, which is believed to act in sequence after TNF-α [38], appears to mediate most of the articular damage in arthritis [21], because it induces proteoglycan degradation and inhibition of proteoglycan synthesis [131]. Also, IL-1 induces the production of the metalloproteases stromelysin and collagenase [21], and enhances bone resorption [132]. In RA, the balance between IL-1 and its physiological inhibitor IL-1 receptor antagonist is shifted in favour of IL-1, indicating a dysregulation that may be crucial in promoting chronicity.

Chemokines

Several studies have documented the existence of a positive feedback between the macrophage-derived TNF-α and IL-1 and chemotactic factors for monocytes, IL-8 and MCP-1 [133]. These factors are produced by synovial macrophages in an autocrine manner [134]. The highest levels of secreted IL-8 are observed in patients with seropositive RA, indicating a correlation with a particularly vigorous macrophage activation [135]. Significantly, IL-8 derived from synovial macrophages is a powerful promoter of angiogenesis, thus providing a link between macrophage activation and the prominent neovascularization of the RA synovium [136].

Anti-inflammatory/regulatory cytokines

Macrophages also generate anti-inflammatory cytokines, most notably IL-1 receptor antagonist and IL-10 (the latter described under Regulatory cytokines, above), both cytokines being engaged in autocrine regulatory loops.

Differentiated macrophages constitutively express IL-1 receptor antagonist, which binds to IL-1 receptors without evoking physiological responses [21]. Significantly, this protein is upregulated by proinflammatory cytokines, including IL-1 itself or GM-CSF, inducing strong anti-inflammatory effects [21]. By means of this feedback mechanism, macrophages can therefore contribute to the termination of inflammatory reactions. The critical relevance of IL-1 in chronic RA [21], as well as the imbalance between IL-1 and IL-1 receptor antagonist, constitute the rationale for apparently successful therapy with IL-1 receptor antagonist [12,21,137].

Cytokines with a dual role in arthritis

Interleukin-6

IL-6 is the most strikingly elevated cytokine in RA, especially in the synovial fluid during acute disease [138]. The acute rise is consistent with the role of IL-6 in acute-phase responses. However, although IL-6 levels in the synovial fluid correlate with the degree of radiological joint damage, and IL-6 and soluble IL-6 receptors promote the generation of osteoclasts [139], this cytokine may also protect cartilage in acute disease but promote excessive bone formation in chronic disease [140]. Although IL-6 is mostly produced by synovial fibroblasts and only partly by macrophages [141], two findings suggest that the striking IL-6 rise is a prominent outcome of macrophage activation: the morphological vicinity of IL-6-expressing fibroblasts with CD14+ macrophages in the RA synovial tissue [141]; and the in vitro and coculture studies [63] that showed that IL-1 stimulates IL-6 production.

Transforming growth factor-β

In RA, different forms of TGF-β and TGF-β receptors are expressed by macrophages in the lining and sublining [142], as well as at the cartilage-pannus junction [143] and in the synovial fluid [144]. TGF-β is a main regulator of connective tissue remodelling, controlling both matrix production and degradation [145]. In experimental animals, TGF-β can induce synovial inflammation, but can also suppress acute and chronic arthritis [144]. In the latter case, TGF-β can act as a regulatory molecule, especially by counteracting some of the effects of IL-1, including metalloprotease production [145] and phagocytosis of collagen [146]. On the other hand, synovial fluid TGF-β induces the expression of the FcγRIII macrophage receptor, the stimulation of which induces release of tissue-damaging reactive oxygen species [147]. The potential relevance of FcγRs for the pathogenesis of arthritis has recently been re-emphasized [148,149]. Likewise, TGF-β is a potent chemotactic factor for leucocytes, promoting monocyte adhesion and possibly resulting in excessive inflammatory infiltration in chronic disease [150]. Another limit to the therapeutic potential of TGF-β is the enhancement of synovial fibroblast proliferation [144].

The inhibiting effects of TGF-β on metalloproteases are also controversial. While inhibition of gelatinase B and collagenase suggest a protective role in tissue destruction [151], the increase collagenase-3 in chondrocytes may aggravate cartilage damage [152]. The effects of TGF-β on TIMP are also ambiguous [153], because the regulation of matrix metalloproteinase and TIMP may depend on different tissue domains (superficial versus deep cartilage layers) and may also vary for intracellular and extracellular digestion of collagen [146,152]. Metalloproteases themselves can also affect TGF-β, by regulating the shedding of latent TGF-β that is attached to decorin [154], and thereby creating a loop that may enhance disease.

Nitric oxide and reactive oxygen species

In RA, variable numbers of synovial lining macrophages may represent a source of NO [155,156]. Synovial cells exposed to NO increase their TNF-α production [156], possibly adding to the mechanisms that promote synovitis [157]. NO may be relevant to arthritis also because of its effects on bone remodelling [158]. However, NO can also exert protective effects in experimental autoimmunity [159], limiting perhaps the antiarthritic impact of selective antagonists for human inducible NO synthase [160].

RA macrophages also produce reactive oxygen species [161], which are involved in distal inflammatory processes. Enhanced mitochondrial production of reactive oxygen species in RA blood monocytes correlates with plasma levels of TNF-α, confirming the stimulatory effect of this cytokine on the production of reactive oxygen species [161].

In general, the link between macrophage activation and molecules with dual activity (be they macrophage products or external stimuli, the latter being soluble, membrane-bound, stimulatory, or suppressive factors) and the number of different receptors that are involved in such stimulation may result not only in potent proinflammatory functions of macrophages, but also in powerful anti-inflammatory and tissue repair functions. Finally, macrophage stimuli and macrophage responses rely heavily on autocrine regulatory mechanisms, which makes it difficult to discern the cause from the effect.

Lessons from experimental models of arthritis

Experimental arthritides with histological similarities to human RA [2] have confirmed the role(s) of macrophages and/or their products in synovitis [2], including the following: macrophage infiltration and activation patterns; migration mechanisms of bone marrow-derived monocytes; maturation into effector and immunoregulatory subpopulations; activation of circulating monocytes and extra-articular macrophages; leading role of TNF-α; sensitivity to cytokine-based therapy, including gene therapy approaches; and sensitivity to reduction of monocyte recruitment or depletion of activated macrophages/osteoclasts.

In addition to the TNF-α transgenic models of arthritis, two recent transgenic manipulations are worth mentioning. The first, a back-cross of TNF-α transgenic mice with arthritis-susceptible DBA/1 mice [162], results in arthritis with enhanced production of TNF-α, IL-1 and IL-6 in the synovial membrane, but with remarkable paucity of macrophage and lymphocyte infiltration. The second, a back-cross of a T-cell receptor transgene with the non-obese diabetes (NOD) strain (K/B × N) [163], is characterized by erosive arthritis with predominant macrophage infiltration and other striking similarities to human RA: synovitis of the distal joints, lymphocyte clustering close to macrophage infiltrates and predominant polymorphonuclear leucocyte exudation in the synovial fluid. Strikingly, the autoantigen recognized by both T cells and B cells in this model has recently been identified as the ubiquitous glycolytic enzyme glucose-6-phosphate isomerase, lending strong support to the concept that general breakage of tolerance can lead to aggressive arthritis [164].

Treatment of human rheumatoid arthritis with conventional antimacrophage approaches

The definition of the role of macrophage-derived cytokines in the perpetuation of RA [2], of the pathophysiological and therapeutic dichotomy between inflammation and cartilage destruction, and of the crucial significance of activated macrophages in the synovial membrane in relationship to permanent joint damage [7] have prompted a radical re-evaluation of the current regimens of anti-inflammatory and disease-modifying treatments. In addition, research concerning conventional agents with antimacrophage effects is now aimed at potentiating such effects.

Disease-modifying antirheumatic therapy

Empirically introduced disease-modifying antirheumatic drugs (DMARDs) possess a whole array of anti-macrophage effects [10].

Gold compounds

Administration of gold compounds to RA patients results in gold accumulation in the lysosomes of synovial macrophages, especially in lysosome-rich sublining macrophages [165]. In monocytes, gold compounds inhibit Fc and C3 receptor expression, oxygen radical generation and IL-1 production [2]. Through their effects on macrophages as accessory cells, gold compounds also inhibit T-cell proliferation in response to antigen or mitogen [2]. Gold compounds inhibit the production of IL-1, IL-8 and MCP-1 [166] and decrease monocyte chemotaxis in vitro [2]. In the synovial lining, this is paralleled by a significant decrease in macrophage numbers and IL-1, IL-6 and TNF-α production [9,10]. In vitro, gold salts also inhibit angiogenic properties of macrophages, probably through their thiol moiety [167], which colocalizes in macrophage lysosomes together with gold [165]. In experimental arthritis, gold salts seem much more effective as long-term disease-modifying drugs than as anti-inflammatory agents [168].

Methotrexate

One of the most effective DMARDs, methotrexate also impairs chemotaxis of blood monocytes [2] and monokine production [169], while increasing the production of cytokine inhibitors, including soluble TNF-α receptor R75. Because methotrexate shifts the IL-1/IL-1 receptor antagonist balance in favour of IL-1 receptor antagonist, this drug may pharmacologically correct the imbalance between these two mediators [169]. A change in the monokine balance, including that of TNF-α [169], may indirectly cause a selective decrease in collagenase production in the synovial tissue. A surprising caveat of methotrexate therapy, however, is the accelerated formation of rheumatoid nodules in some patients [170].

Antimalarials

Antimalarials are endowed with significant antirheumatic effects in early RA [171], but are apparently less effective than gold. They are are attractive because of their limited toxicity. Their tropism for lysosomes [172] is probably the cause for their slow accumulation in macrophages, in which they inhibit the release of arachidonate and the production of prostaglandin E2 via phospholipase A2 inhibition [173]. At high concentrations, antimalarials also inhibit the production of IL-1 and TNF-α in lipopolysaccharide-stimulated macrophages [174].

Corticosteroids

The potent anti-inflammatory effects of corticosteroids in RA can be at least partly explained by transcriptional downregulation of the inflammatory cytokines IL-1 and IL-6, or, as recently reported, transcriptional and post-transcriptional downregulation of TNF-α in monocytes [175]. Corticosteroids may also affect the balance of the functionally distinct membrane-bound and soluble TNF-α [117]. Interestingly, in vitro studies suggest that addition of low doses of IL-4 and IL-10 decreases the dose of corticosteroids that is necessary to downregulate TNF-α, possibly via a coordinated attack on activated macrophages. Corticosteroid also decrease the production of IL-8 and MCP-1 [134,166]; this, once optimally exploited, may limit the self-perpetuating ingress of monocytes into the inflamed joint.

Nonsteroidal anti-inflammatory drugs

Aspirin reduces the production of prostaglandin E2 through acetylation of the isoforms 1 and 2 of the cyclo-oxygenase. Although its use is limited by the gastric side effects (mostly dependent on cyclo-oxygenase-1 inhibition), there is a renewed interest in aspirin derivatives that potently and selectively inactivate the inducible cyclo-oxygenase-2 isoform in isolated macrophages and in local inflammation [15,176]. Cyclo-oxygenase-2-dependent mechanisms selectively induce the production of IL-6 [177], the cytokine that is most highly increased in the RA synovial fluid. Aspirin may affect macrophages also by decreasing the TNF-α production via nuclear factor-κB (NF-κB) mechanisms [178].

Experimental antimacrophage therapy

Counteraction of monocyte/macrophage activation at a cellular level

Leukapheresis

In RA, repeated leukapheresis has proven effective in depleting the bloodstream of activated monocytes [8,54], leading to reduced expression of differentiation markers, DR antigens, cytokines, neopterin and prostaglandin E2 [6,8,54].

Apoptosis-inducing agents

A theoretical way of counteracting activated macrophages or osteoclasts is to eliminate them physically from the inflammatory foci, or from systemic loci that are relevant to disease. Incorporation of liposome-encapsulated bisphosphonates by activated macrophages, for example, induces apoptotic cell death in these cells [179], a process that circumvents secondary tissue damage by restraining cellular organelles in apoptotic vesicles. Systemic application to arthritic rats counteracts not only joint swelling, but also joint destruction and subchondral bone damage [2,180]. The DMARD bucillamine also appears to display apoptotic effects in monocyte lines [181]. Notably, liposome encapsulation can also be exploited for selective delivery of macrophage-modulating drugs [2] and for gene therapy constructs [182].

Control of gene transcription

The transcription of most cytokine genes in monocytes/macrophages depends on the activation of NF-κB and nuclear factor-κM transcription factors [183] or that of the activator protein (AP)-1 complex. In RA synovial macrophages, the expression of NF-κB is much more pronounced than that of AP-1 [184], a selectivity that may bear important therapeutic implications [185]. Accordingly, the antiarthrtic effects of IL-4 may be based on the selective suppression of NF-κB in macrophages [186]. IL-10 also downregulates the production of proinflammatory monokines [187] (see above), inhibiting the nuclear factors NF-κB, AP-1, or nuclear factor-IL-6 [188]. Unlike IL-4, IL-10 can also enhance degradation of the mRNA for IL-1 and TNF-α [189].

Vitamin D3

Vitamin D3 may exert major immunomodulatory effects in RA [190] that are possibly based on the effects on activated synovial macrophages, resulting in positive regulation of the anti-inflammatory cytokines IL-4 and TGF-β [191]. Accordingly, dietary supplementation of vitamin D3 in collagen-induced arthritis suppresses or prevents arthritis [192]. These immunomodulatory effects may directly or indirectly underlie the observation that, in RA, the serum levels of vitamin D3 are inversely correlated with parameters of disease activity [193]. Vitamin D3 supplementation may therefore represent a simple but effective therapy for RA, although it may increase the risk of developing renal concrements [194].

Gene therapy in arthritis

Gene therapy approaches have been applied to counteract IL-1 and TNF-α, cytokines that are predominantly produced by macrophages [182]. Gene therapy with IL-1 receptor antagonist has proven efficacious in a number of experimental arthritis models [182,195,196]. The same applies to therapeutic overexpression of the soluble IL-1 type I receptor-IgG and the type I soluble TNF-α receptor-IgG fusion proteins, although the latter appears less effective [182]. Recently, gene therapy approaches have also been extended to anti-inflammatory cytokines (ie IL-4 [197], IL-10 [182], IL-13 [104] and TGF-β [198]). An interesting approach of gene therapy is to achieve 'molecular synovectomy', either by expression of herpes simplex virus-thymidine kinase, with subsequent administration of ganciclovir [199,200], or by overexpression of Fas ligand, resulting in synovial cell apoptosis [201,202]. Gene therapy aimed at neutralizing proinflammatory macrophage products, overexpressing macrophage-regulating mediators, or simply eliminating overly activated macrophages therefore carries some promise for the treatment of arthritis [203].

Conclusion

Although it is unlikely that macrophages represent the 'initiators' of the pathogenetic cascade in RA, it is believed that these cells act as amplifiers of local and systemic inflammation, with a direct contribution to matrix degradation. Locally, macrophages are involved in recruitment and activation of inflammatory cells, cell contact, or cytokine-mediated activation/differentiation of neighbouring cells, secretion of matrix-degrading enzymes, and neovascularization. At a systemic level, macrophages amplify disease via the acute phase response network, production of TNF-α, development of bone marrow differentiation anomalies, and chronic activation of circulating monocytes.

Although identifying the diease aetiology remains the only means to fully silence RA, efforts to therapeutically address activated monocytes/macrophages have the advantage of striking the very cell population that mediates/amplifies most of the irreversible cartilage destruction, thus minimizing adverse effects on other cells that may have no (or marginal) effects on joint damage. The development of more sophisticated means to reduce the numbers of activated macrophages (eg by selective apoptosis-inducing agents), to inhibit activation signals and/or their specific macrophage receptors, or to selectively counteract the macrophage products that act as disease amplifiers, raises the hope of optimizing the therapeutic success against joint inflammation and irreversible joint damage.

References

  1. 1.

    Bresnihan B: Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol. 1999, 26: 717-719.

    PubMed  Google Scholar 

  2. 2.

    Burmester GR, Stuhlmüller B, Keyszer G, Kinne RW: Mononuclear phagocytes and rheumatoid synovitis. Mastermind or workhorse in arthritis?. Arthritis Rheum. 1997, 40: 5-18.

    PubMed  Google Scholar 

  3. 3.

    Kinne RW, Stuhlmüller B, Palombo-Kinne E, Burmester GR: The role of macrophages in the pathogenesis of rheumatoid arthritis. In: Rheumatoid Arthritis: The New frontiers in Pathogenesis and Treatment. Edited by Wollheim F, Firestein GS, Panayi GS. Oxford: Oxford University Press. 2000, : 69-87.

    Google Scholar 

  4. 4.

    Gracie JA, Forsey RJ, Chan WL: A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest. 1999, 104: 1393-1401.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Michaelsson E, Holmdahl M, Engstrom A: Macrophages, but not dendritic cells, present collagen to T cells. Eur J Immunol. 1995, 25: 2234-2241.

    PubMed  Google Scholar 

  6. 6.

    Stuhlmüller B, Ungethüm U, Scholze S: Identification of known and novel genes in activated monocytes from patients with rheumatoid arthritis. Arthritis Rheum. 2000, 43: 775-790.

    PubMed  Google Scholar 

  7. 7.

    Mulherin D, Fitzgerald O, Bresnihan B: Synovial tissue macrophage populations and articular damage in rheumatoid arthritis. Arthritis Rheum. 1996, 39: 115-124.

    PubMed  Google Scholar 

  8. 8.

    Hahn G, Stuhlmüller B, Hain N: Modulation of monocyte activation in patients with rheumatoid arthritis by leukapheresis therapy. J Clin Invest. 1993, 91: 862-870.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Yanni G, Nabil M, Farahat MR, Poston RN, Panayi GS: Intramuscular gold decreases cytokine expression and macrophage numbers in the rheumatoid synovial membrane. Ann Rheum Dis. 1994, 53: 315-322.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Bondeson J: The mechanisms of action of disease-modifying antirheumatic drugs: a review with emphasis on macrophage signal transduction and the induction of proinflammatory cytokines. Gen Pharmacol. 1997, 29: 127-150.

    PubMed  Google Scholar 

  11. 11.

    Feldmann M, Bondeson J, Brennan FM, Foxwell BM, Maini RN: The rationale for the current boom in anti-TNFalpha treatment. Is there an effective means to define therapeutic targets for drugs that provide all the benefits of anti-TNFalpha and minimise hazards?. Ann Rheum Dis. 1999, 58(suppl 1): 127-131.

    Google Scholar 

  12. 12.

    Bresnihan B, Alvaro-Gracia JM, Cobby M: Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum. 1998, 41: 2196-2204.

    PubMed  Google Scholar 

  13. 13.

    Bondeson J, Browne KA, Brennan FM, Foxwell BM, Feldmann M: Selective regulation of cytokine induction by adenoviral gene transfer of IkappaBalpha into human macrophages: lipopolysac-charide-induced, but not zymosan-induced, proinflammatory cytokines are inhibited, but IL-10 is nuclear factor-kappaB independent. J Immunol. 1999, 162: 2939-2945.

    PubMed  Google Scholar 

  14. 14.

    Wadsworth SA, Cavender DE, Beers SA: RWJ 67657, a potent, orally active inhibitor of p38 mitogen-activated protein kinase. J Pharmacol Exp Ther. 1999, 291: 680-687.

    PubMed  Google Scholar 

  15. 15.

    Crofford LJ, Lipsky PE, Brooks P: Current comment: basic biology and clinical application of specific cyclooxygenase-2 inhibitors. Arthritis Rheum. 2000, 43: 4-13.

    PubMed  Google Scholar 

  16. 16.

    Hogg N, Palmer DG, Revell PA: Mononuclear phagocytes of normal and rheumatoid synovial membrane identified by monoclonal antibodies. Immunology. 1985, 56: 673-681.

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Pirila L, Heino J: Altered integrin expression in rheumatoid synovial lining type B cells: in vitro cytokine regulation of alpha 1 beta 1, alpha 6 beta 1, and alpha v beta 5 integrins. J Rheumatol. 1996, 23: 1691-1698.

    PubMed  Google Scholar 

  18. 18.

    Klareskog L, Forsum U, Kabelitz D: Immune functions of human synovial cells. Phenotypic and T cell regulatory properties of macrophage-like cells that express HLA-DR. Arthritis Rheum. 1982, 25: 488-501.

    PubMed  Google Scholar 

  19. 19.

    van den Berg TK, van Die I, de Lavalette CR: Regulation of sialoadhesin expression on rat macrophages. Induction by gluco-corticoids and enhancement by IFN-beta, IFN-gamma, IL-4, and lipopolysaccharide. J Immunol. 1996, 157: 3130-3138.

    PubMed  Google Scholar 

  20. 20.

    Kinne RW, Schmidt-Weber CB, Hoppe R: Long-term amelioration of rat adjuvant arthritis following systemic elimination of macrophages by clodronate-containing liposomes. Arthritis Rheum. 1995, 38: 1777-1790.

    PubMed  Google Scholar 

  21. 21.

    Arend WP, Malyak M, Guthridge CJ, Gabay C: Interleukin-1 receptor antagonist: Role in biology. Annu Rev Immunol. 1998, 16: 27-55.

    PubMed  Google Scholar 

  22. 22.

    Miossec P, van den Berg W: Th1/Th2 cytokine balance in arthritis. Arthritis Rheum. 1997, 40: 2105-2115.

    PubMed  Google Scholar 

  23. 23.

    Koch AE: Review: angiogenesis: implications for rheumatoid arthritis. Arthritis Rheum. 1998, 41: 951-962.

    PubMed  Google Scholar 

  24. 24.

    Khalkhali-Ellis Z, Roodman ST, Knutsen AP: Expression of macrophage markers by a population of T cells obtained from synovial fluid of a subgroup of patients with juvenile rheumatoid arthritis. J Rheumatol. 1998, 25: 352-360.

    PubMed  Google Scholar 

  25. 25.

    Hirohata S, Yanagida T, Itoh K: Accelerated generation of CD14+ monocyte-lineage cells from the bone marrow of rheumatoid arthritis patients. Arthritis Rheum. 1996, 39: 836-843.

    PubMed  Google Scholar 

  26. 26.

    Kotake S, Higaki M, Sato K: Detection of myeloid precursors (granulocyte/macrophage colony forming units) in the bone marrow adjacent to rheumatoid arthritis joints. J Rheumatol. 1992, 19: 1511-1516.

    PubMed  Google Scholar 

  27. 27.

    Jongen-Lavrencic M, Peeters HR, Wognum A: Elevated levels of inflammatory cytokines in bone marrow of patients with rheumatoid arthritis and anemia of chronic disease. J Rheumatol. 1997, 24: 1504-1509.

    PubMed  Google Scholar 

  28. 28.

    Santiago-Schwarz F, Sullivan C, Rappa D, Carsons SE: Distinct alterations in lineage committed progenitor cells exist in the peripheral blood of patients with rheumatoid arthritis and primary Sjogren's syndrome. J Rheumatol. 1996, 23: 439-446.

    PubMed  Google Scholar 

  29. 29.

    Horie S, Nakada K, Masuyama J: Detection of large macrophage colony forming cells in the peripheral blood of patients with rheumatoid arthritis. J Rheumatol. 1997, 24: 1517-1521.

    PubMed  Google Scholar 

  30. 30.

    Lee BO, Ishihara K, Denno K: Elevated levels of the soluble form of bone marrow stromal cell antigen 1 in the sera of patients with severe rheumatoid arthritis. Arthritis Rheum. 1996, 39: 629-637.

    PubMed  Google Scholar 

  31. 31.

    De Benedetti F, Pignatti P, Massa M: Soluble tumour necrosis factor receptor levels reflect coagulation abnormalities in systemic juvenile chronic arthritis. Br J Rheumatol. 1997, 36: 581-588.

    PubMed  Google Scholar 

  32. 32.

    Klimiuk PA, Goronzy JJ, Bjor NJ, Beckenbaugh RD, Weyand CM: Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol. 1997, 151: 1311-1319.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Palmer DG, Hogg N, Highton J, Hessian PA, Denholm I: Macrophage migration and maturation within rheumatoid nodules. Arthritis Rheum. 1987, 30: 728-736.

    PubMed  Google Scholar 

  34. 34.

    Hamilton JA: Rheumatoid arthritis: opposing actions of haemopoietic growth factors and slow-acting anti-rheumatic drugs. Lancet. 1993, 342: 536-539.

    PubMed  Google Scholar 

  35. 35.

    Wicks I, Cooley H, Szer J: Autologous hemopoietic stem cell transplantation: a possible cure for rheumatoid arthritis?. Arthritis Rheum. 1997, 40: 1005-1011.

    PubMed  Google Scholar 

  36. 36.

    Iguchi T, Kurosaka M, Ziff M: Electron microscopic study of HLA-DR and monocyte/macrophage staining cells in the rheumatoid synovial membrane. Arthritis Rheum. 1986, 29: 600-613.

    PubMed  Google Scholar 

  37. 37.

    Tak PP, Smeets TJ, Daha MR: Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum. 1997, 40: 217-225.

    PubMed  Google Scholar 

  38. 38.

    Feldmann M, Brennan FM, Maini RN: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol. 1996, 14: 397-440.

    PubMed  Google Scholar 

  39. 39.

    Alsalameh S, Winter K, Al-Ward R: Distribution of TNF-alpha, TNF-R55 and TNF-R75 in the rheumatoid synovial membrane: TNF receptors are localized preferentially in the lining layer; TNF-alpha is distributed mainly in the vicinity of TNF receptors in the deeper layers. Scand J Immunol. 1999, 49: 278-285. 10.1046/j.1365-3083.1999.00458.x.

    PubMed  Google Scholar 

  40. 40.

    Pettit AR, Thomas R: Dendritic cells: the driving force behind autoimmunity in rheumatoid arthritis?. Immunol Cell Biol. 1999, 77: 420-427. 10.1046/j.1440-1711.1999.00855.x.

    PubMed  Google Scholar 

  41. 41.

    Tetlow LC, Lees M, Ogata Y, Nagase H, Woolley DE: Differential expression of gelatinase B (MMP-9) and stromelysin-1 (MMP- 3) by rheumatoid synovial cells in vitro and in vivo. Rheumatol Int. 1993, 13: 53-59.

    PubMed  Google Scholar 

  42. 42.

    Ahrens D, Koch AE, Pope RM, Stein-Picarella M, Niedbala MJ: Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1576-1587.

    PubMed  Google Scholar 

  43. 43.

    Gravallese EM, Harada Y, Wang JT: Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am J Pathol. 1998, 152: 943-951.

    PubMed  PubMed Central  Google Scholar 

  44. 44.

    Highton J, Carlisle B, Palmer DG: Changes in the phenotype of monocytes/macrophages and expression of cytokine mRNA in peripheral blood and synovial fluid of patients with rheumatoid arthritis. Clin Exp Immunol. 1995, 102: 541-546.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Bomalaski JS, Clark MA, Zurier RB: Enhanced phospholipase activity in peripheral blood monocytes from patients with rheumatoid arthritis. Arthritis Rheum. 1986, 29: 312-318.

    PubMed  Google Scholar 

  46. 46.

    Schulze-Koops H, Davis LS, Kavanaugh AF, Lipsky PE: Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation. Arthritis Rheum. 1997, 40: 639-647.

    PubMed  Google Scholar 

  47. 47.

    Liote F, Boval-Boizard B, Weill D, Kuntz D, Wautier JL: Blood monocyte activation in rheumatoid arthritis: Increased monocyte adhesiveness, integrin expression, and cytokine release. Clin Exp Immunol. 1996, 106: 13-19.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Reibnegger G, Egg D, Fuchs D: Urinary neopterin reflects clinical activity in patients with rheumatoid arthritis. Arthritis Rheum. 1986, 29: 1063-1070.

    PubMed  Google Scholar 

  49. 49.

    Gruber BL, Sorbi D, French DL: Markedly elevated serum MMP-9 (gelatinase B) levels in rheumatoid arthritis: a potentially useful laboratory marker. Clin Immunol Immunopathol. 1996, 78: 161-171. 10.1006/clin.1996.0025.

    PubMed  Google Scholar 

  50. 50.

    Heller RA, Schena M, Chai A: Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc Natl Acad Sci USA. 1997, 94: 2150-2155.

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Steven MM, Lennie SE, Sturrock RD, Gemmell CG: Enhanced bacterial phagocytosis by peripheral blood monocytes in rheumatoid arthritis. Ann Rheum Dis. 1984, 43: 435-439.

    PubMed  PubMed Central  Google Scholar 

  52. 52.

    Mazure G, Fernandes T, McCarthy DA: Blood monocytes in rheumatoid arthritis are highly adherent to cultured endothelium. Int Arch Allergy Immunol. 1995, 108: 211-223.

    PubMed  Google Scholar 

  53. 53.

    Okawa-Takatsuji M, Aotsuka S, Uwatoko S, Yokohari R, Inagaki K: Monocyte-mediated suppression of rheumatoid factor production in normal subjects. Clin Immunol Immunopathol. 1988, 46: 195-204.

    PubMed  Google Scholar 

  54. 54.

    Nagashima M, Yoshino S, Tanaka H: Granulocyte and monocyte apheresis suppresses symptoms of rheumatoid arthritis: a pilot study. Rheumatol Int. 1998, 18: 113-118.

    PubMed  Google Scholar 

  55. 55.

    Kirkpatrick RB, Emery JG, Connor JR: Induction and expression of human cartilage glycoprotein 39 in rheumatoid inflammatory and peripheral blood monocyte-derived macrophages. Exp Cell Res. 1997, 237: 46-54. 10.1006/excr.1997.3764.

    PubMed  Google Scholar 

  56. 56.

    Krause SW, Rehli M, Andreesen R: Carboxypeptidase M as a marker of macrophage maturation. Immunol Rev. 1998, 161: 119-127.

    PubMed  Google Scholar 

  57. 57.

    Stout RD, Suttles J: T cell signaling of macrophage function in inflammatory disease. Front Biosci. 1997, 2: d197-206.

    PubMed  Google Scholar 

  58. 58.

    Dayer J-M, Burger D: Cytokines and direct cell contact in synovitis: relevance to therapeutic intervention [commentary].

  59. 59.

    Lacraz S, Isler P, Vey E, Welgus HG, Dayer J-M: Direct contact between T lymphocytes and monocytes is a major pathway for induction of metalloproteinase expression. J Biol Chem. 1994, 269: 22027-22033.

    PubMed  Google Scholar 

  60. 60.

    Landis RC, Friedman ML, Fisher RI, Ellis TM: Induction of human monocyte IL-1 mRNA and secretion during anti-CD3 mitogenesis requires two distinct T cell-derived signals. J Immunol. 1991, 146: 128-135.

    PubMed  Google Scholar 

  61. 61.

    Parry SL, Sebbag M, Feldmann M, Brennan FM: Contact with T cells modulates monocyte IL-10 production: Role of T cell membrane TNF-alpha. J Immunol. 1997, 158: 3673-3681.

    PubMed  Google Scholar 

  62. 62.

    Sebbag M, Parry SL, Brennan FM, Feldmann M: Cytokine stimulation of T lymphocytes regulates their capacity to induce monocyte production of tumor necrosis factor-alpha, but not interleukin-10: possible relevance to pathophysiology of rheumatoid arthritis. Eur J Immunol. 1997, 27: 624-632.

    PubMed  Google Scholar 

  63. 63.

    Chomarat P, Rissoan MC, Pin JJ, Banchereau J, Miossec P: Contribution of IL-1, CD14, and CD13 in the increased IL-6 production induced by in vitro monocyte-synoviocyte interactions. J Immunol. 1995, 155: 3645-3652.

    PubMed  Google Scholar 

  64. 64.

    Janusz MJ, Hare M: Cartilage degradation by cocultures of transformed macrophage and fibroblast cell lines. A model of metallo-proteinase-mediated connective tissue degradation. J Immunol. 1993, 150: 1922-1931.

    PubMed  Google Scholar 

  65. 65.

    Scott BB, Weisbrot LM, Greenwood JD: Rheumatoid arthritis synovial fibroblast and U937 macrophage/monocyte cell line interaction in cartilage degradation. Arthritis Rheum. 1997, 40: 490-498.

    PubMed  Google Scholar 

  66. 66.

    McInnes IB, Al-Mughales J, Field M: The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis. Nature Med. 1996, 2: 175-182.

    PubMed  Google Scholar 

  67. 67.

    McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY: Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nature Med. 1997, 3: 189-195.

    PubMed  Google Scholar 

  68. 68.

    Badolato R, Ponzi AN, Millesimo M, Notarangelo LD, Musso T: Interleukin-15 (IL-15) induces IL-8 and monocyte chemotactic protein 1 production in human monocytes. Blood. 1997, 90: 2804-2809.

    PubMed  Google Scholar 

  69. 69.

    Jovanovic DV, DiBattista JA, Martel-Pelletier J: IL-17 stimulates the production and expression of proinflammatory cytokines, IL-1beta and TNF-alpha, by human macrophages. J Immunol. 1998, 160: 3513-3521.

    PubMed  Google Scholar 

  70. 70.

    Aarvak T, Chabaud M, Miossec P, Natvig JB: IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol. 1999, 162: 1246-1251.

    PubMed  Google Scholar 

  71. 71.

    Kotake S, Udagawa N, Takahashi N: IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J Clin Invest. 1999, 103: 1345-1352.

    PubMed  PubMed Central  Google Scholar 

  72. 72.

    Shalom-Barak T, Quach J, Lotz M: Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF- kappaB. J Biol Chem. 1998, 273: 27467-27473.

    PubMed  Google Scholar 

  73. 73.

    Dinarello CA: Interleukin-18. Methods. 1999, 19: 121-132. 10.1006/meth.1999.0837.

    PubMed  Google Scholar 

  74. 74.

    Rodenburg RJ, Brinkhuis RF, Peek R: Expression of macrophage-derived chemokine (MDC) mRNA in macrophages is enhanced by interleukin-1beta, tumor necrosis factor alpha, and lipopolysaccharide. J Leukoc Biol. 1998, 63: 606-611.

    PubMed  Google Scholar 

  75. 75.

    Edwards CK, Zhou T, Zhang J: Inhibition of superantigen-induced proinflammatory cytokine production and inflammatory arthritis in MRL-lpr/lpr mice by a transcriptional inhibitor of TNF-alpha. J Immunol. 1996, 157: 1758-1772.

    PubMed  Google Scholar 

  76. 76.

    Chatterjee D, Khoo KH: Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects. Glycobiology. 1998, 8: 113-120. 10.1093/glycob/8.2.113.

    PubMed  Google Scholar 

  77. 77.

    Yoshida A, Koide Y: Arabinofuranosyl-terminated and mannosylated lipoarabinomannans from Mycobacterium tuberculosis induce different levels of interleukin-12 expression in murine macrophages. Infect Immun. 1997, 65: 1953-1955.

    PubMed  PubMed Central  Google Scholar 

  78. 78.

    Bernardo J, Billingslea AM, Blumenthal RL: Differential responses of human mononuclear phagocytes to mycobacterial lipoarabinomannans: role of CD14 and the mannose receptor. Infect Immun. 1998, 66: 28-35.

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Linn ML, Aaskov JG, Suhrbier A: Antibody-dependent enhancement and persistence in macrophages of an arbovirus associated with arthritis. J Gen Virol. 1996, 77: 407-411.

    PubMed  Google Scholar 

  80. 80.

    Wilkerson MJ, Davis WC, Baszler TV, Cheevers WP: Immunopathology of chronic lentivirus-induced arthritis. Am J Pathol. 1995, 146: 1433-1443.

    PubMed  PubMed Central  Google Scholar 

  81. 81.

    Itescu S: Rheumatic aspects of acquired immunodeficiency syndrome. Curr Opin Rheumatol. 1996, 8: 346-353.

    PubMed  Google Scholar 

  82. 82.

    Takahashi Y, Murai C, Shibata S: Human parvovirus B19 as a causative agent for rheumatoid arthritis. Proc Natl Acad Sci USA. 1998, 95: 8227-8232.

    PubMed  PubMed Central  Google Scholar 

  83. 83.

    Cutolo M: Do sex hormones modulate the synovial macrophages in rheumatoid arthritis?. Ann Rheum Dis. 1997, 56: 281-284.

    PubMed  PubMed Central  Google Scholar 

  84. 84.

    Rittenhouse PA, Redei E: Thyroxine administration prevents streptococcal cell wall-induced inflammatory responses. Endocrinology. 1997, 138: 1434-1439.

    PubMed  Google Scholar 

  85. 85.

    Wilder RL, Elenkov IJ: Hormonal regulation of tumor necrosis factor-alpha, interleukin-12 and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus?. Ann N Y Acad Sci. 1999, 876: 14-31.

    PubMed  Google Scholar 

  86. 86.

    Miossec P, Naviliat M, Dupuy DA, Sany J, Banchereau J: Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthritis Rheum. 1990, 33: 1180-1187.

    PubMed  Google Scholar 

  87. 87.

    Isomaki P, Luukkainen R, Saario R, Toivanen P, Punnonen J: Interleukin-10 functions as an antiinflammatory cytokine in rheumatoid synovium. Arthritis Rheum. 1996, 39: 386-395.

    PubMed  Google Scholar 

  88. 88.

    Hart PH, Hunt EK, Bonder CS, Watson CJ, Finlay-Jones JJ: Regulation of surface and soluble TNF receptor expression on human monocytes and synovial fluid macrophages by IL-4 and IL-10. J Immunol. 1996, 157: 3672-3680.

    PubMed  Google Scholar 

  89. 89.

    Allen JB, Wong HL, Costa GL, Bienkowski MJ, Wahl SM: Suppression of monocyte function and differential regulation of IL-1 and IL-1ra by IL-4 contribute to resolution of experimental arthritis. J Immunol. 1993, 151: 4344-4351.

    PubMed  Google Scholar 

  90. 90.

    Sugiyama E, Taki H, Kuroda A, Bienkowski MJ, Wahl SM: Interleukin-4 inhibits prostaglandin E2 production by freshly prepared adherent rheumatoid synovial cells via inhibition of biosynthesis and gene expression of cyclo-oxygenase II but not of cyclo-oxygenase I. Ann Rheum Dis. 1996, 55: 375-382.

    PubMed  PubMed Central  Google Scholar 

  91. 91.

    Kuroda A, Sugiyama E, Taki H, Mino T, Kobayashi M: Interleukin-4 inhibits the gene expression and biosynthesis of cytosolic phospholipase A2 in lipopolysaccharide stimulated U937 macrophage cell line and freshly prepared adherent rheumatoid synovial cells. Biochem Biophys Res Commun. 1997, 230: 40-43. 10.1006/bbrc.1996.5885.

    PubMed  Google Scholar 

  92. 92.

    Rocken M, Urban J, Shevach EM: Antigen-specific activation, tolerization, and reactivation of the interleukin 4 pathway in vivo. J Exp Med. 1994, 179: 1885-1893.

    PubMed  Google Scholar 

  93. 93.

    Abbas AK, Murphy KM, Sher A: Functional diversity of helper T lymphocytes. Nature. 1996, 383: 787-793.

    PubMed  Google Scholar 

  94. 94.

    Kasama T, Strieter RM, Lukacs NW: Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest. 1995, 95: 2868-2876.

    PubMed  PubMed Central  Google Scholar 

  95. 95.

    Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M: Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med. 1994, 179: 1517-1527.

    PubMed  Google Scholar 

  96. 96.

    Keystone E, Wherry J, Grint P: IL-10 as a therapeutic strategy in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am. 1998, 24: 629-639.

    PubMed  Google Scholar 

  97. 97.

    Smeets TJ, Kraan MC, Versendaal J, Breedveld FC, Tak PP: Analysis of serial synovial biopsies in patients with rheumatoid arthritis: description of a control group without clinical improvement after treatment with interleukin 10 or placebo. J Rheumatol. 1999, 26: 2089-2093.

    PubMed  Google Scholar 

  98. 98.

    Hermann JA, Hall MA, Maini RN, Feldmann M, Brennan FM: Important immunoregulatory role of interleukin-11 in the inflammatory process in rheumatoid arthritis. Arthritis Rheum. 1998, 41: 1388-1397.

    PubMed  Google Scholar 

  99. 99.

    Trepicchio WL, Dorner AJ: Interleukin-11. A gp130 cytokine. Ann N Y Acad Sci. 1998, 856: 12-21.

    PubMed  Google Scholar 

  100. 100.

    Mino T, Sugiyama E, Taki H: Interleukin-1alpha and tumor necrosis factor alpha synergistically stimulate prostaglandin E2-dependent production of interleukin-11 in rheumatoid synovial fibroblasts. Arthritis Rheum. 1998, 41: 2004-2013.

    PubMed  Google Scholar 

  101. 101.

    Walmsley M, Butler DM, Marinova-Mutafchieva L, Feldmann M: An anti-inflammatory role for interleukin-11 in established murine collagen-induced arthritis. Immunology. 1998, 95: 31-37.

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Thornton S, Duwel LE, Boivin GP, Ma Y, Hirsch R: Association of the course of collagen-induced arthritis with distinct patterns of cytokine and chemokine messenger RNA expression. Arthritis Rheum. 1999, 42: 1109-1118.

    PubMed  Google Scholar 

  103. 103.

    Schwertschlag US, Trepicchio WL, Dykstra KH: Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. Leukemia. 1999, 13: 1307-1315. 10.1038/sj/leu/2401514.

    PubMed  Google Scholar 

  104. 104.

    Bessis N, Boissier MC, Ferrara P: Attenuation of collagen-induced arthritis in mice by treatment with vector cells engineered to secrete interleukin-13. Eur J Immunol. 1996, 26: 2399-2403.

    PubMed  Google Scholar 

  105. 105.

    Isomaki P, Luukkainen R, Toivanen P, Punnonen J: The presence of interleukin-13 in rheumatoid synovium and its antiinflammatory effects on synovial fluid macrophages from patients with rheumatoid arthritis. Arthritis Rheum. 1996, 39: 1693-1702.

    PubMed  Google Scholar 

  106. 106.

    Ogasawara H, Takeda-Hirokawa N, Sekigawa I: Inhibitory effect of interleukin-16 on interleukin-2 production by CD4+ T cells. Immunology. 1999, 96: 215-219. 10.1046/j.1365-2567.1999.00693.x.

    PubMed  PubMed Central  Google Scholar 

  107. 107.

    Franz JK, Kolb SA, Hummel KM: Interleukin-16, produced by synovial fibroblasts, mediates chemoattraction for CD4+ T lymphocytes in rheumatoid arthritis. Eur J Immunol. 1998, 28: 2661-2671. 10.1002/(SICI)1521-4141(199809)28:09<2661::AID-IMMU2661>3.0.CO;2-N.

    PubMed  Google Scholar 

  108. 108.

    Klimiuk PA, Goronzy JJ, Weyand CM: IL-16 as an anti-inflammatory cytokine in rheumatoid synovitis. J Immunol. 1999, 162: 4293-4299.

    PubMed  Google Scholar 

  109. 109.

    Dayer J-M, Fenner H: The role of cytokines and their inhibitors in arthritis. Baillieres Clin Rheumatol. 1992, 6: 485-516.

    PubMed  Google Scholar 

  110. 110.

    Firestein GS, Alvaro-Gracia JM, Maki R: Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol. 1990, 144: 3347-3353.

    PubMed  Google Scholar 

  111. 111.

    Müssener A, Klareskog L, Lorentzen JC, Kleinau S: TNF-alpha dominates cytokine mRNA expression in lymphoid tissues of rats developing collagen- and oil-induced arthritis. Scand J Immunol. 1995, 42: 128-134.

    PubMed  Google Scholar 

  112. 112.

    Schmidt-Weber CB, Pohlers D, Siegling A: Cytokine gene activation in synovial membrane, regional lymph nodes, and spleen during the course of rat adjuvant arthritis. Cell Immunol. 1999, 195: 53-65. 10.1006/cimm.1999.1509.

    PubMed  Google Scholar 

  113. 113.

    Schädlich H, Ermann J, Biskop M: Anti-inflammatory effects of systemic anti-tumour necrosis factor alpha treatment in human/murine SCID arthritis. Ann RheumDis. 1999, 58: 428-434.

    Google Scholar 

  114. 114.

    Henderson B, Pettipher ER: Arthritogenic actions of recombinant IL-1 and tumour necrosis factor alpha in the rabbit: evidence for synergistic interactions between cytokines in vivo. Clin Exp Immunol. 1989, 75: 306-310.

    PubMed  PubMed Central  Google Scholar 

  115. 115.

    Probert L, Plows D, Kontogeorgos G, Kollias G: The type I interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF-transgenic mice. Eur J Immunol. 1995, 25: 1794-1797.

    PubMed  Google Scholar 

  116. 116.

    Neidel J, Schulze M, Lindschau J: Association between degree of bone-erosion and synovial fluid-levels of tumor necrosis factor alpha in the knee-joints of patients with rheumatoid arthritis. Inflamm Res. 1995, 44: 217-221.

    PubMed  Google Scholar 

  117. 117.

    Grell M, Douni E, Wajant H: The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995, 83: 793-802.

    PubMed  Google Scholar 

  118. 118.

    Georgopoulos S, Plows D, Kollias G: Transmembrane TNF is sufficient to induce localized tissue toxicity and chronic inflammatory arthritis in transgenic mice. J Inflamm. 1996, 46: 86-97.

    PubMed  Google Scholar 

  119. 119.

    Alexopoulou L, Pasparakis M, Kollias G: A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling. Eur J Immunol. 1997, 27: 2588-2592.

    PubMed  Google Scholar 

  120. 120.

    Gearing AJ, Beckett P, Christodoulou M: Processing of tumour necrosis factor-alpha precursor by metalloproteinases. Nature. 1994, 370: 555-557.

    PubMed  Google Scholar 

  121. 121.

    Roux-Lombard P, Punzi L, Hasler F: Soluble tumor necrosis factor receptors in human inflammatory synovial fluids. Arthritis Rheum. 1993, 36: 485-489.

    PubMed  Google Scholar 

  122. 122.

    Grell M, Wajant H, Zimmermann G, Scheurich P: The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc Natl Acad Sci USA. 1998, 95: 570-575.

    PubMed  PubMed Central  Google Scholar 

  123. 123.

    Su X, Zhou T, Yang P, Edwards CK, Mountz JD: Reduction of arthritis and pneumonitis in motheaten mice by soluble tumor necrosis factor receptor. Arthritis Rheum. 1998, 41: 139-149.

    PubMed  Google Scholar 

  124. 124.

    Ulfgren AK, Andersson U, Engstrom M, Klareskog L, Maini RN, Taylor PC: Systemic anti-TNFα therapy in rheumatoid arthritis (RA) down-regulates synovial TNFα synthesis. Arthritis Rheum. 1999, 42: S94-.

    Google Scholar 

  125. 125.

    Kavanaugh A, Schaible T, deWoody K: Long-term follow-up of patients treated with infliximab (anti-TNFα antibody) in clinical trials. Arthritis Rheum. 1999, 42: S401-.

    Google Scholar 

  126. 126.

    Rau R, Herborn G, Sander O: Long-term treatment with the fully human anti-TNF-antibody D2E7 slows radiographic disease progression in rheumatoid arthritis. Arthritis Rheum. 1999, 42: S400-.

    Google Scholar 

  127. 127.

    Lipsky P, St Clair W, Furst D: 54-week clinical and radiographic results from the ATTRACT trial: a phase III study of Infliximab (Remicade TM) in patients with active RA despite methotrexate. Arthritis Rheum. 1999, 42: S401-.

    Google Scholar 

  128. 128.

    Mackay F, Loetscher H, Stueber D, Gehr G, Lesslauer W: Tumor necrosis factor alpha (TNF-alpha)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55. J Exp Med. 1993, 177: 1277-1286.

    PubMed  Google Scholar 

  129. 129.

    Paleolog E: Target effector role of vascular endothelium in the inflammatory response: Insights from the clinical trial of anti-TNF alpha antibody in rheumatoid arthritis. Mol Pathol. 1997, 50: 225-233.

    PubMed  PubMed Central  Google Scholar 

  130. 130.

    Wood NC, Dickens E, Symons JA, Duff GW: In situ hybridization of interleukin-1 in CD14-positive cells in rheumatoid arthritis. Clin Immunol Immunopathol. 1992, 62: 295-300.

    PubMed  Google Scholar 

  131. 131.

    von den Hoff H, de Koning M, van Kampen J, van der Korst J: Interleukin-1 reversibly inhibits the synthesis of biglycan and decorin in intact articular cartilage in culture. J Rheumatol. 1995, 22: 1520-1526.

    PubMed  Google Scholar 

  132. 132.

    Assuma R, Oates T, Cochran D, Amar S, Graves DT: IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immunol. 1998, 160: 403-409.

    PubMed  Google Scholar 

  133. 133.

    Bedard PA, Golds EE: Cytokine-induced expression of mRNAs for chemotactic factors in human synovial cells and fibroblasts. J Cell Physiol. 1993, 154: 433-441.

    PubMed  Google Scholar 

  134. 134.

    Loetscher P, Dewald B, Baggiolini M, Seitz M: Monocyte chemoat-tractant protein 1 and interleukin 8 production by rheumatoid synoviocytes. Effects of anti-rheumatic drugs. Cytokine. 1994, 6: 162-170.

    PubMed  Google Scholar 

  135. 135.

    Peichl P, Ceska M, Effenberger F: Presence of NAP-1/IL-8 in synovial fluids indicates a possible pathogenic role in rheumatoid arthritis. Scand J Immunol. 1991, 34: 333-339.

    PubMed  Google Scholar 

  136. 136.

    Koch AE, Polverini PJ, Kunkel SL: Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992, 258: 1798-1801.

    PubMed  Google Scholar 

  137. 137.

    Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M: Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group. Arthritis Rheum. 1996, 39: 1092-1101.

    PubMed  Google Scholar 

  138. 138.

    Houssiau FA, Devogelaer JP, Van Damme J, de Deuxchaisnes CN, Van Snick J: Interleukin-6 in synovial fluid and serum of patients with rheumatoid arthritis and other inflammatory arthritides. Arthritis Rheum. 1988, 31: 784-788.

    PubMed  Google Scholar 

  139. 139.

    Kotake S, Sato K, Kim KJ: Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996, 11: 88-95.

    PubMed  Google Scholar 

  140. 140.

    Van De Loo FA, Kuiper S, van Enckevort FH, Arntz OJ, van den Berg WB: Interleukin-6 reduces cartilage destruction during experimental arthritis. A study in interleukin-6-deficient mice. Am J Pathol. 1997, 151: 177-191.

    PubMed  PubMed Central  Google Scholar 

  141. 141.

    Wood NC, Symons JA, Dickens E, Duff GW: In situ hybridization of IL-6 in rheumatoid arthritis. Clin Exp Immunol. 1992, 87: 183-189.

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Szekanecz Z, Haines GK, Harlow LA: Increased synovial expression of transforming growth factor (TGF)-beta receptor endoglin and TGF-beta 1 in rheumatoid arthritis: possible interactions in the pathogenesis of the disease. Clin Immunol Immunopathol. 1995, 76: 187-194. 10.1006/clin.1995.1114.

    PubMed  Google Scholar 

  143. 143.

    Chu CQ, Field M, Abney E: Transforming growth factor-beta 1 in rheumatoid synovial membrane and cartilage/pannus junction. Clin Exp Immunol. 1991, 86: 380-386.

    PubMed  PubMed Central  Google Scholar 

  144. 144.

    Wahl SM, Allen JB, Wong HL, Dougherty SF, Ellingsworth LR: Antagonistic and agonistic effects of transforming growth factor-beta and IL-1 in rheumatoid synovium. J Immunol. 1990, 145: 2514-2519.

    PubMed  Google Scholar 

  145. 145.

    Edwards DR, Murphy G, Reynolds JJ: Transforming growth factor beta modulates the expression of collagenase and metallo-proteinase inhibitor. EMBO J. 1987, 6: 1899-1904.

    PubMed  PubMed Central  Google Scholar 

  146. 146.

    van der Zee E, Everts V, Beertsen W: Cytokines modulate routes of collagen breakdown. Review with special emphasis on mechanisms of collagen degradation in the periodontium and the burst hypothesis of periodontal disease progression. J Clin Periodontol. 1997, 24: 297-305.

    PubMed  Google Scholar 

  147. 147.

    Wahl SM, Allen JB, Welch GR, Wong HL: Transforming growth factor-beta in synovial fluids modulates Fc gamma RII (CD16) expression on mononuclear phagocytes. J Immunol. 1992, 148: 485-490.

    PubMed  Google Scholar 

  148. 148.

    Nieto A, Caliz R, Pascual M, Mataran L, Garcia S, Martin J: Involvement of Fcγ receptor IIIA genotypes in susceptibility to rheumatoid arthritis. Arthritis Rheum. 2000, 43: 735-739.

    PubMed  Google Scholar 

  149. 149.

    van Lent PLEM, van Vuuren AJ, Blom AR: Role of Fc receptor γ chain in inflammation and cartilage damage during experimental antigen-induced arthritis. Arthritis Rheum. 2000, 43: 740-752.

    PubMed  Google Scholar 

  150. 150.

    Wahl SM, Allen JB, Weeks BS, Wong HL, Klotman PE: Transforming growth factor beta enhances integrin expression and type IV collagenase secretion in human monocytes. Proc Natl Acad Sci USA. 1993, 90: 4577-4581.

    PubMed  PubMed Central  Google Scholar 

  151. 151.

    Suto TS, Fine LG, Shimizu F, Kitamura M: In vivo transfer of engineered macrophages into the glomerulus: endogenous TGF-beta-mediated defense against macrophage-induced glomerular cell activation. J Immunol. 1997, 159: 2476-2483.

    PubMed  Google Scholar 

  152. 152.

    Moldovan F, Pelletier JP, Hambor J, Cloutier JM, Martel-Pelletier J: Collagenase-3 (matrix metalloprotease 13) is preferentially localized in the deep layer of human arthritic cartilage in situ: In vitro mimicking effect by transforming growth factor beta. Arthritis Rheum. 1997, 40: 1653-1661.

    PubMed  Google Scholar 

  153. 153.

    Alexander JP, Samples JR, Acott TS: Growth factor and cytokine modulation of trabecular meshwork matrix metalloproteinase and TIMP expression. Curr Eye Res. 1998, 17: 276-285.

    PubMed  Google Scholar 

  154. 154.

    Imai K, Hiramatsu A, Fukushima D, Pierschbacher MD, Okada Y: Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. Biochem J. 1997, 322: 809-814.

    PubMed  PubMed Central  Google Scholar 

  155. 155.

    Sakurai H, Kohsaka H, Liu MF: Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides. J Clin Invest. 1995, 96: 2357-2363.

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    McInnes IB, Leung BP, Field M: Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients. J Exp Med. 1996, 184: 1519-1524.

    PubMed  Google Scholar 

  157. 157.

    Amin AR, Attur MG, Thakker GD: A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci USA. 1996, 93: 14014-14019.

    PubMed  PubMed Central  Google Scholar 

  158. 158.

    Chae HJ, Park RK, Chung HT: Nitric oxide is a regulator of bone remodelling. J Pharm Pharmacol. 1997, 49: 897-902.

    PubMed  Google Scholar 

  159. 159.

    Bogdan C: The multiplex function of nitric oxide in (auto)immunity. J Exp Med. 1998, 187: 1361-1365.

    PubMed  PubMed Central  Google Scholar 

  160. 160.

    Hansen DWJ, Peterson KB, Trivedi M: 2-Iminohomopiperidinium salts as selective inhibitors of inducible nitric oxide synthase (iNOS). J Med Chem. 1998, 41: 1361-1366. 10.1021/jm9704715.

    PubMed  Google Scholar 

  161. 161.

    Miesel R, Murphy MP, Kröger H: Enhanced mitochondrial radical production in patients which rheumatoid arthritis correlates with elevated levels of tumor necrosis factor alpha in plasma. Free Radic Res. 1996, 25: 161-169.

    PubMed  Google Scholar 

  162. 162.

    Butler DM, Malfait AM, Mason LJ: DBA/1 mice expressing the human TNF-alpha transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition. J Immunol. 1997, 159: 2867-2876.

    PubMed  Google Scholar 

  163. 163.

    Kouskoff V, Korganow AS, Duchatelle V: Organ-specific disease provoked by systemic autoimmunity. Cell. 1996, 87: 811-822.

    PubMed  Google Scholar 

  164. 164.

    Matsumoto I, Staub A, Benoist C, Mathis D: Arthritis provoked by linked T and B cell recognition of a glycolytic enzyme. Science. 1999, 286: 1732-1735. 10.1126/science.286.5445.1732.

    PubMed  Google Scholar 

  165. 165.

    Nakamura H, Igarashi M: Localization of gold in synovial membrane of rheumatoid arthritis treated with sodium aurothiomalate. Studies by electron microscope and electron probe x-ray microanalysis. Ann Rheum Dis. 1977, 36: 209-215.

    PubMed  PubMed Central  Google Scholar 

  166. 166.

    Seitz M, Loetscher P, Dewald B, Towbin H, Baggiolini M: In vitro modulation of cytokine, cytokine inhibitor, and prostaglandin E release from blood mononuclear cells and synovial fibroblasts by antirheumatic drugs. J Rheumatol. 1997, 24: 1471-1476.

    PubMed  Google Scholar 

  167. 167.

    Koch AE, Burrows JC, Polverini PJ, Cho M, Leibovich SJ: Thiol-containing compounds inhibit the production of monocyte/macrophage-derived angiogenic activity. Agents Actions. 1991, 34: 350-357.

    PubMed  Google Scholar 

  168. 168.

    Lewis EJ, Bishop J, Aspinall SJ: A simple inflammation model that distinguishes between the actions of anti-inflammatory and antirheumatic drugs. Inflamm Res. 1998, 47: 26-35. 10.1007/s000110050251.

    PubMed  Google Scholar 

  169. 169.

    Seitz M, Loetscher P, Dewald B: Methotrexate action in rheumatoid arthritis: Stimulation of cytokine inhibitor and inhibition of chemokine production by peripheral blood mononuclear cells. Br J Rheumatol. 1995, 34: 602-609.

    PubMed  Google Scholar 

  170. 170.

    Williams FM, Cohen PR, Arnett FC: Accelerated cutaneous nodulosis during methotrexate therapy in a patient with rheumatoid arthritis. J Am Acad Dermatol. 1998, 39: 359-362.

    PubMed  Google Scholar 

  171. 171.

    Clark P, Casas E, Tugwell P: Hydroxychloroquine compared with placebo in rheumatoid arthritis. A randomized controlled trial. Ann Intern Med. 1993, 119: 1067-1071.

    PubMed  Google Scholar 

  172. 172.

    MacIntyre AC, Cutler DJ: Role of lysosomes in hepatic accumulation of chloroquine. J Pharm Sci. 1988, 77: 196-199.

    PubMed  Google Scholar 

  173. 173.

    Angel J, Colard O, Chevy F, Fournier C: Interleukin-1-mediated phospholipid breakdown and arachidonic acid release in human synovial cells. Arthritis Rheum. 1993, 36: 158-167.

    PubMed  Google Scholar 

  174. 174.

    Jeong JY, Jue DM: Chloroquine inhibits processing of tumor necrosis factor in lipopolysaccharide-stimulated RAW 264.7 macrophages. J Immunol. 1997, 158: 4901-4907.

    PubMed  Google Scholar 

  175. 175.

    Amano Y, Lee SW, Allison AC: Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta, and interleukin-6: mediation by decreased mRNA stability. Mol Pharmacol. 1993, 43: 176-182.

    PubMed  Google Scholar 

  176. 176.

    Kalgutkar AS, Crews BC, Rowlinson SW: Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science. 1998, 280: 1268-1270.

    PubMed  Google Scholar 

  177. 177.

    Ross SE, Williams RO, Mason LJ: Suppression of TNF-alpha expression, inhibition of Th1 activity, and amelioration of collagen-induced arthritis by rolipram. J Immunol. 1997, 159: 6253-6259.

    PubMed  Google Scholar 

  178. 178.

    Shackelford RE, Alford PB, Xue Y: Aspirin inhibits tumor necrosis factor alpha gene expression in murine tissue macrophages. Mol Pharmacol. 1997, 52: 421-429.

    PubMed  Google Scholar 

  179. 179.

    Schmidt-Weber CB, Rittig M, Buchner E: Apoptotic cell death in activated monocytes following incorporation of clodronate-liposomes. J Leukoc Biol. 1996, 60: 230-244.

    PubMed  Google Scholar 

  180. 180.

    Oelzner P, Bräuer R, Henzgen S: Periarticular bone alterations in chronic antigen-induced arthritis: free and liposome-encapsulated clodronate prevent loss of bone mass in the secondary spongiosa. Clin Immunol Immunopathol. 1999, 90: 79-88.

    Google Scholar 

  181. 181.

    Sawada T, Hashimoto S, Furukawa H: Generation of reactive oxygen species is required for bucillamine, a novel anti-rheumatic drug, to induce apoptosis in concert with copper. Immunopharmacology. 1997, 35: 195-202. 10.1016/S0162-3109(96)00145-2.

    PubMed  Google Scholar 

  182. 182.

    Evans CH, Ghivizzani SC, Lechman ER: Lessons learned from gene transfer approaches.

  183. 183.

    Foxwell B, Browne K, Bondeson J: Efficient adenoviral infection with IkappaB alpha reveals that macrophage tumor necrosis factor alpha production in rheumatoid arthritis is NF-kappaB dependent. Proc Natl Acad Sci USA. 1998, 95: 8211-8215.

    PubMed  PubMed Central  Google Scholar 

  184. 184.

    Handel ML, McMorrow LB, Gravallese EM: Nuclear factor-kappa B in rheumatoid synovium. Localization of p50 and p65. Arthritis Rheum. 1995, 38: 1762-1770.

    PubMed  Google Scholar 

  185. 185.

    Handel ML: Transcription factors AP-1 and NF-kappa B: where steroids meet the gold standard of anti-rheumatic drugs. Inflamm Res. 1997, 46: 282-286. 10.1007/s000110050188.

    PubMed  Google Scholar 

  186. 186.

    Donnelly RP, Crofford LJ, Freeman SL: Tissue-specific regulation of IL-6 production by IL-4. Differential effects of IL-4 on nuclear factor-kappa B activity in monocytes and fibroblasts. J Immunol. 1993, 151: 5603-5612.

    PubMed  Google Scholar 

  187. 187.

    Chomarat P, Banchereau J, Miossec P: Differential effects of interleukins 10 and 4 on the production of interleukin-6 by blood and synovium monocytes in rheumatoid arthritis. Arthritis Rheum. 1995, 38: 1046-1054.

    PubMed  Google Scholar 

  188. 188.

    Wang P, Wu P, Siegel MI, Egan RW, Billah MM: Interleukin (IL)-10 inhibits nuclear factor kappa B (NF kappa B) activation in human monocytes. IL-10 and IL-4 suppress cytokine synthesis by different mechanisms. J Biol Chem. 1995, 270: 9558-9563.

    PubMed  Google Scholar 

  189. 189.

    Bogdan C, Paik J, Vodovotz Y, Nathan C: Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem. 1992, 267: 23301-23308.

    PubMed  Google Scholar 

  190. 190.

    DeLuca HF, Zierold C: Mechanisms and functions of vitamin D. Nutr Rev. 1998, 56 (suppl): S4-S10.

    Google Scholar 

  191. 191.

    Cantorna MT, Woodward WD, Hayes CE, DeLuca HF: 1,25-dihy-droxyvitamin D3 is a positive regulator for the two anti-encephalitogenic cytokines TGF-beta 1 and IL-4. J Immunol. 1998, 160: 5314-5319.

    PubMed  Google Scholar 

  192. 192.

    Tsuji M, Fujii K, Nakano T, Nishii Y: 1 alpha-hydroxyvitamin D3 inhibits type II collagen-induced arthritis in rats. FEBS Lett. 1994, 337: 248-250.

    PubMed  Google Scholar 

  193. 193.

    Oelzner P, Müller A, Deschner F: Relationship between disease activity and serum levels of vitamin D metabolites and PTH in rheumatoid arthritis. Calcif Tissue Int. 1998, 62: 193-198. 10.1007/s002239900416.

    PubMed  Google Scholar 

  194. 194.

    Ito S, Nozawa S, Ishikawa H: Renal stones in patients with rheumatoid arthritis. J Rheumatol. 1997, 24: 2123-2128.

    PubMed  Google Scholar 

  195. 195.

    van Meurs JB, van Lent PL, Singer II: Interleukin-1 receptor antagonist prevents expression of the metalloproteinase-generated neoepitope VDIPEN in antigen-induced arthritis. Arthritis Rheum. 1998, 41: 647-656.

    PubMed  Google Scholar 

  196. 196.

    Baragi VM, Renkiewicz RR, Jordan H: Transplantation of transduced chondrocytes protects articular cartilage from interleukin 1-induced extracellular matrix degradation. J Clin Invest. 1995, 96: 2454-2460.

    PubMed  PubMed Central  Google Scholar 

  197. 197.

    Lubberts E, Joosten LA, van den Bersselaar L: Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction. J Immunol. 1999, 163: 4546-4556.

    PubMed  Google Scholar 

  198. 198.

    Glansbeek HL, van Beuningen HM, Vitters EL, van der Kraan PM, van den Berg WB: Stimulation of articular cartilage repair in established arthritis by local administration of transforming growth factor-beta into murine knee joints. Lab Invest. 1998, 78: 133-142.

    PubMed  Google Scholar 

  199. 199.

    Sant SM, Suarez TM, Moalli MR: Molecular lysis of synovial lining cells by in vivo herpes simplex virus-thymidine kinase gene transfer. Hum Gene Ther. 1998, 9: 2735-2743.

    PubMed  Google Scholar 

  200. 200.

    Goossens PH, Schouten GJ, 't Hart BA: Feasibility of adenovirus-mediated nonsurgical synovectomy in collagen- induced arthritis-affected rhesus monkeys. Hum Gene Ther. 1999, 10: 1139-1149. 10.1089/10430349950018139.

    PubMed  Google Scholar 

  201. 201.

    Guery L, Batteux F, Bessis N: Expression of fas ligand improves the effect of IL-4 in collagen-induced arthritis. Eur J Immunol. 2000, 30: 308-315. 10.1002/(SICI)1521-4141(200001)30:01<308::AID-IMMU308>3.3.CO;2-9.

    PubMed  Google Scholar 

  202. 202.

    Okamoto K, Asahara H, Kobayashi T: Induction of apoptosis in the rheumatoid synovium by Fas ligand gene transfer. Gene Ther. 1998, 5: 331-338. 10.1038/sj/gt/3300597.

    PubMed  Google Scholar 

  203. 203.

    Muller-Ladner U, Evans CH, Franklin BN: Gene transfer of cytokine inhibitors into human synovial fibroblasts in the SCID mouse model. Arthritis Rheum. 1999, 42: 490-497.

    PubMed  Google Scholar 

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Acknowledgements

Elke Kunisch and Stefan Sickinger are gratefully acknowledged for critical discussion, and Mrs Börbel Ukena for providing and sorting the literature. RW Kinne, R Bräuer, B Stuhlmüller and GR Burmester were supported by grants from the German Federal Ministry of Education and Research (BMBF; 01ZZ9602 and 01-VM-9705/6).

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Affiliations

  1. Friedrich Schiller University, Jena, Germany

    Raimund W Kinne, Rolf Bräuer & Ernesta Palombo-Kinne

  2. Humboldt University of Berlin, Berlin, Germany

    Bruno Stuhlmüller & Gerd-R Burmester

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  1. Raimund W Kinne
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  2. Rolf Bräuer
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  3. Bruno Stuhlmüller
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  4. Ernesta Palombo-Kinne
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  5. Gerd-R Burmester
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Kinne, R.W., Bräuer, R., Stuhlmüller, B. et al. Macrophages in rheumatoid arthritis. Arthritis Res Ther 2, 189 (2000). https://doi.org/10.1186/ar86

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Keywords

  • cytokine
  • fibroblast
  • macrophage
  • monocyte
  • nitric oxide
  • peripheral blood
  • reactive oxygen species
  • rheumatoid arthritis
  • synovial membrane
  • T-cell

Arthritis Research & Therapy

ISSN: 1478-6362

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