- Open Access
SLE - Complex cytokine effects in a complex autoimmune disease: tumor necrosis factor in systemic lupus erythematosus
Arthritis Res Thervolume 5, Article number: 172 (2003)
Tumor necrosis factor (TNF) is a proinflammatory cytokine and a B-cell growth factor. It has numerous possible effects on T lymphocytes and dendritic cells, and it influences apoptosis. These differential effects may in part explain why patients under TNF-blocker therapy can develop autoantibodies to nuclear antigens, and may shed some light on the finding that low TNF fosters autoimmune disease in some mouse strains. On the contrary, TNF is increased in the blood and in the inflamed kidneys of systemic lupus erythematosus patients. Several studies in lupus-prone mice other than the F1 generation of New Zealand Black mice crossed with New Zealand White mice suggest that TNF is highly proinflammatory in the efferent limb and is potentially detrimental in lupus organ disease. Therefore, TNF blockade probably constitutes an efficacious therapeutic option.
Serum tumor necrosis factor (TNF) levels in human systemic lupus erythematosus (SLE) are increased [1–4]. In spite of likewise increased soluble TNF receptors (TNF-R1 and TNF-R2), this increased TNF is bioactive . While these findings could open the door for TNF-blocking therapy, TNF exerts several different effects and TNF blockade may have a variety of consequences.
There are two main reasons for some concern about using TNF blocking therapies in SLE patients. First, patients with either rheumatoid arthritis or Crohn's disease sometimes develop antinuclear antibodies and IgM antibodies to double-stranded DNA in the course of TNF-blocking therapies [6–8]. These patients only rarely develop a lupus-like syndrome, however, and both clinical symptoms and autoantibodies disappear when anti-TNF treatment is stopped in such patients [6, 7]. Nevertheless, the propensity to induce pathogenic antibodies to nuclear antigens could constitute a serious problem in SLE.
The second reason for concern is that the F1 generation of New Zealand Black mice with New Zealand White (NZB/W) mice not only develops autoantibodies and a lupus-like disease, but also has a clearly diminished production of TNF . In concordance with this observation, New Zealand Black mice, which suffer from mild lupus, also develop severe disease when rendered deficient in TNF . Furthermore, therapeutic application of TNF in NZB/W mice showed significant benefit: high-dose TNF given early in life delayed the development of autoantibodies and lupus nephritis [9, 11]. A deficiency of TNF thus apparently fosters autoimmunity and disease in these mice, but it is unclear how this relates to human disease  and to other murine models of SLE with higher TNF production.
The numerous possible roles of TNF in autoimmunity are somewhat difficult to define not only by virtue of the multiple biological effects of TNF, but also due to different effects in different models and under different settings. However, although it is undisputed that this cytokine is importantly involved in the context of autoimmunity, TNF may indeed play more than one role [13–17]. In fact, many functions of TNF are well defined, and we shall try to discuss the different possible effects that TNF may have on the pathogenesis of SLE.
Both membrane-bound TNF and secreted TNF are important in the development of secondary lymphoid organ structures, such as in lymph nodes, in the spleen and in Peyer's patches. Deficiency of TNF results in the absence of germinal centers and in the absence of follicular dendritic cells. In particular, TNF cooperates with lymphotoxin in secondary lymphoid tissue development and also mediates signals for primary B-cell follicle generation [18–20]. While membrane-bound TNF confers the major structure of secondary lymphoid organs, soluble TNF appears to be involved in the generation of primary B-cell follicles . Low levels of TNF may thus be associated with aberrant B-cell responses .
Furthermore, TNF influences T-cell receptor signaling, and TNF deficiency could also contribute to aberrant immune reactivities through this additional pathway early on in development and/or in the course of disease induction . The level of TNF expression both in its membrane-associated form as well as in its soluble form thus contributes importantly to the development of T cells, of B cells and of dendritic cells (see later), and to the interactions between these cells, and it may constitute one important determinant of the type and level of immune responses.
TNF exerts a wide variety of relevant immunoregulatory functions on a variety of cells of the innate and adaptive immune system. TNF is a growth factor for B lymphocytes, and B lymphocytes are able to produce significant amounts of TNF in an autocrine loop [24–26]. It is of interest that this autocrine TNF production is induced by ligation of CD40, a possible therapeutic target in SLE [27–29], and is prevented by cyclosporin A, another therapeutic agent for SLE . Moreover, stimulation of murine lupus (MRL/lpr) B cells by membrane-bound TNF via their TNF-R2 provides a signal that overcomes the lack of CD40 ligand (CD154) otherwise necessary for the production of (auto)antibodies . TNF may also exert a significant influence on B cells by virtue of its capacity to induce IL-6 . The effects of IL-6 on multiple aspects of B-cell development and activation as well as on SLE have been well established . IL-6 may also affect B cells via T helper type 1 and T helper type 2 cells, the differentiation of which IL-6 is also able to influence .
The potential of TNF to modify T-cell receptor signaling has already been briefly mentioned. Interestingly, short-term stimulation of activated T lymphocytes with TNF results in further activation and proliferation [35–37]. Moreover, TNF stimulation leads to increased production of IFN-γ , a cytokine with a clear-cut pathological role in SLE [38–40].
In addition, chronic TNF exposure induces a reversible loss of the surface T-cell receptor complex, and thus T-cell hyporesponsiveness [41, 42], but still allows for IL-2-mediated proliferation. Since similar effects in rheumatoid arthritis patients are readily reversed by anti-TNF therapy , this normalization of T-cell hyporesponsiveness in patients treated with TNF-blocking agents may also influence the induction of autoantibodies.
TNF also constitutes an activating cytokine and a maturation factor of dendritic cells, which are essential in immune regulation  and have also been implicated in autoimmunity in general, and SLE in particular [44, 45]. The numbers of both myeloid and plasmacytoid dendritic cells are reduced in the peripheral blood of SLE patients [46, 47]. These dendritic cell counts (or numbers) negatively correlate with the patients' soluble TNF-R2 levels , which in turn correlate with TNF levels .
These findings together suggest that dendritic cells have been matured by TNF and hence are found in lymphoid organs rather than in the peripheral blood. On the contrary, IFN-α produced by lymphoid dendritic cells is another important maturation factor for dendritic cells and is thought to be involved in SLE pathogenesis . However, TNF is able to inhibit the production of IFN-α .
It is interesting that aged NZB/W mice behave differently, in that they have increased numbers of circulating dendritic cells that can be matured by TNF . This is probably due to the decreased systemic TNF production described in NZB/W mice .
The connection of TNF to cell death is already indicated by its name. Indeed, the pro-apoptotic properties of the cytokine, mediated mainly via TNF-R1 but possibly also via TNF-R2, are well established [51–54]. By virtue of also being able to activate anti-apoptotic pathways, and NF-κB in particular, however, TNF can also inhibit apoptosis by inducing a variety of anti-apoptotic molecules, such as inhibitor of apoptosis, TNF-receptor associated factor, and FLICE-like inhibitory protein [52–57]. Rheumatoid arthritis synovial cells are just one example where TNF appears to use such pathways to block Fas-mediated programmed cell death [58, 59]. In concordance with these findings, induction of a stress response, which acts mostly via the same signal transduction molecules as TNF, inhibits apoptosis .
Therefore, while lymphocytes of SLE patients die when stimulated with high concentrations of TNF in vitro and while serum TNF apparently is associated with the increased in vitro lymphocyte apoptosis rate typical of SLE , the in vivo role of TNF in this respect is not clear. In fact, the observation of decreased apoptosis rates upon addition of autologous plasma  rather suggests that the propensity to undergo apoptosis in vitro may be due to cytokine withdrawal afflicting in vivo activated cells .
Theoretically, an abrupt fall in bioactive TNF, as induced by therapeutic TNF blockade, could thus lead to increased Fas-mediated apoptosis. The subsequent exposure of the immune system to more apoptotic material might then be involved in inducing the aforementioned occurrence of antibodies to nuclear antigens during TNF-blocking therapy [6, 7].
However, the notion that TNF can counteract Fas may also be important in another regard. Given that in several mouse strains mutations of Fas (lpr) or FasL (gld) cause severe lupus-like disease by preventing FasL-induced apoptosis [62, 63], protection against Fas-induced apoptosis by TNF may foster autoimmunity. Along these lines, TNF is indeed necessary for sustaining the gld phenotype .
We have so far concentrated on aspects of TNF in the afferent limb of the immune response (Fig. 1, upper part), which suggest that TNF may promote a derangement of immune regulation and be one factor potentially responsible for autoantibody induction. However, TNF is the most important proinflammatory cytokine and a harbinger of tissue destruction. In fact, in contrast to the complex role of TNF in apoptosis and in immune regulation, its powerful proinflammatory effects are unequivocal and have been numerously reviewed .
In this regard, murine and human data on systemic lupus arrive at the same conclusions. First, MRL/lpr mice have high TNF in their serum as well as in their nephritic kidneys, and both serum and renal TNF are correlated with disease activity [66–68]. Also, anti-TNF therapy in MRL/lpr mice [69, 70], in motheaten mice  and in C3H.SW mice  is beneficial. Moreover, even in NZB/W mice, TNF application only delays and does not prevent death from lupus . Finally, even NZB/W kidneys contain remarkably high amounts of TNF once glomerulonephritis is established, and low dosages of TNF administered in late NZB/W disease accelerate renal damage [73, 74].
All these data suggest that TNF is pivotally involved in the tissue destruction observed in lupus organ disease. These conclusions are further supported by observations that macrophages are induced to produce high levels of TNF by immune complexes . Since murine lupus like human SLE constitutes an immune complex-mediated disease and since large amounts of immune complexes are deposited in the glomeruli, it is highly unlikely that the TNF expressed in renal tissue confers protective effects. It rather portends what TNF expression in different tissues is usually for: inflammation and consecutive tissue injury.
As in experimental lupus, TNF is highly expressed in glomeruli in all forms of lupus nephritis [76–79], and the degree of TNF expression correlates with renal inflammatory activity , as measured by a histological activity index. This correlation again suggests involvement of TNF in the inflammatory and destructive process of the disease. These data are further supported by the finding that infliximab significantly reduced proteinuria, one of the hallmarks of active lupus nephritis, in two patients treated with this TNF blocker for a short period of time . However, longer term follow up and careful observation of potential adverse events (which were not seen hitherto) are mandatory. All these data together indicate that TNF plays a detrimental proinflammatory role in SLE organ involvement (Fig. 1, lower part).
Understanding how the immune system integrates the pleiotropic properties of TNF is a challenge, particularly so in diseases like SLE. TNF is both a proinflammatory cytokine and an immunoregulatory cytokine. TNF has differential effects on B cells, on T cells and on dendritic cells as well as on the process of programmed cell death.
These complex properties may explain why TNF blockade can induce increases in antinuclear antibodies and at the same time rapidly reduce inflammation and prevent inflammation-induced damage, also observed in SLE patients. These properties also explain why TNF deficiency may foster systemic autoimmunity under some circumstances, as seen in the NZB/W mice, but why lupus autoantibodies also occur in mice with increased TNF .
TNF is therefore a cytokine with two roles in SLE: its capacity as a prime immune regulator, and its capacity as a proinflammatory mediator. In the afferent limb of the immunoinflammatory response, with its role in lymphoid organ structure development and cellular interactions therein, as well as its influence on B cells, on T cells and on dendritic cells, TNF can modulate an autoimmune response; blocking TNF therefore may or may not be wise (Fig. 1). In the efferent limb of the response, TNF clearly induces inflammation and local injury. With respect to the local injury, blocking TNF should be highly beneficial (Fig. 1).
A critical view on all of these aspects will be necessary to further increase our understanding of the role of TNF in SLE. In the end, however, it is clinical trials that will put all hypotheses to their most relevant tests.
interleukininMRL/lpr: murine lupus
F1 generation of New Zealand Black with New Zealand White mice
systemic lupus erythematosus
tumor necrosis factor
tumor necrosis factor receptor.
Maury CP, Teppo AM: Tumor necrosis factor in the serum of patients with systemic lupus erythematosus. Arthritis Rheum. 1989, 32: 146-150.
Studnicka-Benke A, Steiner G, Petera P, Smolen JS: Tumour necrosis factor alpha and its soluble receptors parallel clinical disease and autoimmune activity in systemic lupus erythematosus. Br J Rheumatol. 1996, 35: 1067-1074. 10.1093/rheumatology/35.11.1067.
Gabay C, Cakir N, Moral F, Roux-Lombard P, Meyer O, Dayer JM, Vischer T, Yazici H, Guerne PA: Circulating levels of tumor necrosis factor soluble receptors in systemic lupus erythematosus are significantly higher than in other rheumatic diseases and correlate with disease activity. J Rheumatol. 1997, 24: 303-308.
Aringer M, Stummvoll GH, Steiner G, Koller M, Steiner CW, Hofler E, Hiesberger H, Smolen JS, Graninger WB: Serum interleukin-15 is elevated in systemic lupus erythematosus. Rheumatology (Oxford). 2001, 40: 876-881. 10.1093/rheumatology/40.8.876.
Aringer M, Feierl E, Steiner G, Stummvoll GH, Höfler E, Steiner CW, Radda I, Smolen JS, Graninger WB: Increased bioactive TNF in human systemic lupus erythematosus: associations with cell death. Lupus. 2002, 11: 102-108. 10.1191/0961203302lu160oa.
Smolen J, Steiner G, Breedveld FC, Kalden JR, Lipsky PE, Maini RN: Anti-TNF therapy and drug induced lupus-like syndrome [abstract]. Ann Rheum Dis. 1999, 58 (suppl 1): 217-
Charles PJ, Smeenk RJ, De Jong J, Feldmann M, Maini RN: Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum. 2000, 43: 2383-2390. 10.1002/1529-0131(200011)43:11<2383::AID-ANR2>3.3.CO;2-4.
Mohan AK, Edwards ET, Cote TR, Siegel JN, Braun MM: Drug-induced systemic lupus erythematosus and TNF-alpha blockers [letter]. Lancet. 2002, 360: 646-10.1016/S0140-6736(02)09800-8.
Jacob CO, McDevitt HO: Tumour necrosis factor-alpha in murine autoimmune 'lupus' nephritis. Nature. 1988, 331: 356-358. 10.1038/331356a0.
Kontoyiannis D, Kollias G: Accelerated autoimmunity and lupus nephritis in NZB mice with an engineered heterozygous deficiency in tumor necrosis factor. Eur J Immunol. 2000, 30: 2038-2047. 10.1002/1521-4141(200007)30:7<2038::AID-IMMU2038>3.0.CO;2-K.
Gordon C, Ranges GE, Greenspan JS, Wofsy D: Chronic therapy with recombinant tumor necrosis factor-alpha in autoimmune NZB/NZW F1 mice. Clin Immunol Immunopathol. 1989, 52: 421-434. 10.1016/0090-1229(89)90157-8.
Pisetsky DS: Tumor necrosis factor alpha blockers and the induction of anti-DNA autoantibodies. Arthritis Rheum. 2000, 43: 2381-2382. 10.1002/1529-0131(200011)43:11<2381::AID-ANR1>3.0.CO;2-M.
O'Shea JJ, Ma A, Lipsky P: Cytokines and autoimmunity. Nature Rev Immunol. 2002, 2: 37-45. 10.1038/nri702.
Mageed RA, Isenberg DA: Tumour necrosis factor alpha in systemic lupus erythematosus and anti-DNA autoantibody production. Lupus. 2002, 11: 850-855. 10.1191/0961203302lu306rr.
Theofilopoulos AN, Lawson BR: Tumour necrosis factor and other cytokines in murine lupus. Ann Rheum Dis. 1999, 58 (suppl 1): I49-I55.
Ettinger R, Mebius R, Browning JL, Michie SA, van Tuijl S, Kraal G, van Ewijk W, McDevitt HO: Effects of tumor necrosis factor and lymphotoxin on peripheral lymphoid tissue development. Int Immunol. 1998, 10: 727-741. 10.1093/intimm/10.6.727.
Jacob CO: Tumor necrosis factor alpha in autoimmunity: pretty girl or old witch?. Immunol Today. 1992, 13: 122-125. 10.1016/0167-5699(92)90107-I.
Wang Y, Wang J, Sun Y, Wu Q, Fu YX: Complementary effects of TNF and lymphotoxin on the formation of germinal center and follicular dendritic cells. J Immunol. 2001, 166: 330-337.
Ettinger R: The role of tumor necrosis factor and lymphotoxin in lymphoid organ development. Curr Top Microbiol Immunol. 2000, 251: 203-210.
Fu YX, Chaplin DD: Development and maturation of secondary lymphoid tissues. Annu Rev Immunol. 1999, 17: 399-433. 10.1146/annurev.immunol.17.1.399.
Ruuls SR, Hoek RM, Ngo VN, McNeil T, Lucian LA, Janatpour MJ, Korner H, Scheerens H, Hessel EM, Cyster JG, McEvoy LM, Sedgwick JD: Membrane-bound TNF supports secondary lymphoid organ structure but is subservient to secreted TNF in driving autoimmune inflammation. Immunity. 2001, 15: 533-543. 10.1016/S1074-7613(01)00215-1.
Vinuesa CG, Cook MC: The molecular basis of lymphoid architecture and B cell responses: implications for immunodeficiency and immunopathology. Curr Mol Med. 2001, 1: 689-725. 10.2174/1566524013363276.
McDevitt H, Munson S, Ettinger R, Wu A: Multiple roles for tumor necrosis factor-alpha and lymphotoxin alpha/beta in immunity and autoimmunity. Arthritis Res. 2002, 4 (suppl 3): S141-S152. 10.1186/ar570.
Kehrl JH, Miller A, Fauci AS: Effect of tumor necrosis factor alpha on mitogen-activated human B cells. J Exp Med. 1987, 166: 786-791. 10.1084/jem.166.3.786.
Boussiotis VA, Nadler LM, Strominger JL, Goldfeld AE: Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells. Proc Natl Acad Sci USA. 1994, 91: 7007-7011.
Rieckmann P, Tuscano JM, Kehrl JH: Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in B-lymphocyte function. Methods. 1997, 11: 128-132. 10.1006/meth.1996.0396.
Mohan C, Shi Y, Laman JD, Datta SK: Interaction between CD40 and its ligand gp39 in the development of murine lupus nephritis. J Immunol. 1995, 154: 1470-1480.
Early GS, Zhao W, Burns CM: Anti-CD40 ligand antibody treatment prevents the development of lupus-like nephritis in a subset of New Zealand black × New Zealand white mice. Response correlates with the absence of an anti-antibody response. J Immunol. 1996, 157: 3159-3164.
Strand V: Monoclonal antibodies and other biologic therapies. Lupus. 2001, 10: 216-221. 10.1191/096120301669817290.
Griffiths B, Emery P: The treatment of lupus with cyclosporin A. Lupus. 2001, 10: 165-170. 10.1191/096120301672970034.
Fujii T, Okada M, Mimori T, Craft J: The transmembrane form of TNF-alpha drives autoantibody production in the absence of CD154: studies using MRL/Mp-Fas(lpr) mice. Clin Exp Immunol. 2002, 130: 224-232. 10.1046/j.1365-2249.2002.01982.x.
Vanden Berghe W, Vermeulen L, De Wilde G, De Bosscher K, Boone E, Haegeman G: Signal transduction by tumor necrosis factor and gene regulation of the inflammatory cytokine interleukin-6. Biochem Pharmacol. 2000, 60: 1185-1195. 10.1016/S0006-2952(00)00412-3.
Cross JT, Benton HP: The roles of interleukin-6 and interleukin-10 in B cell hyperactivity in systemic lupus erythematosus. Inflamm Res. 1999, 48: 255-261. 10.1007/s000110050456.
Diehl S, Rincon M: The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 2002, 39: 531-536. 10.1016/S0161-5890(02)00210-9.
Scheurich P, Thoma B, Ucer U, Pfizenmaier K: Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol. 1987, 138: 1786-1790.
Zucali JR, Elfenbein GJ, Barth KC, Dinarello CA: Effects of human interleukin 1 and human tumor necrosis factor on human T lymphocyte colony formation. J Clin Invest. 1987, 80: 772-777.
Yokota S, Geppert TD, Lipsky PE: Enhancement of antigen- and mitogen-induced human T lymphocyte proliferation by tumor necrosis factor-alpha. J Immunol. 1988, 140: 531-536.
Machold KP, Smolen JS: Interferon-gamma induced exacerbation of systemic lupus erythematosus. J Rheumatol. 1990, 17: 831-832.
Graninger WB, Hassfeld W, Pesau BB, Machold KP, Zielinski CC, Smolen JS: Induction of systemic lupus erythematosus by interferon-gamma in a patient with rheumatoid arthritis. J Rheumatol. 1991, 18: 1621-1622.
Theofilopoulos AN, Koundouris S, Kono DH, Lawson BR: The role of IFN-gamma in systemic lupus erythematosus: a challenge to the Th1/Th2 paradigm in autoimmunity. Arthritis Res. 2001, 3: 136-141. 10.1186/ar290.
Isomaki P, Panesar M, Annenkov A, Clark JM, Foxwell BM, Chernajovsky Y, Cope AP: Prolonged exposure of T cells to TNF down-regulates TCR zeta and expression of the TCR/CD3 complex at the cell surface. J Immunol. 2001, 166: 5495-5507.
Cope AP: Studies of T-cell activation in chronic inflammation. Arthritis Res. 2002, 4 (suppl 3): S197-S211. 10.1186/ar557.
Menges M, Rossner S, Voigtlander C, Schindler H, Kukutsch NA, Bogdan C, Erb K, Schuler G, Lutz MB: Repetitive injections of dendritic cells matured with tumor necrosis factor alpha induce antigen-specific protection of mice from autoimmunity. J Exp Med. 2002, 195: 15-21. 10.1084/jem.20011341.
Palucka AK, Banchereau J, Blanco P, Pascual V: The interplay of dendritic cell subsets in systemic lupus erythematosus. Immunol Cell Biol. 2002, 80: 484-488. 10.1046/j.1440-1711.2002.01112.x.
Drakesmith H, Chain B, Beverley P: How can dendritic cells cause autoimmune disease?. Immunol Today. 2000, 21: 214-217. 10.1016/S0167-5699(00)01610-8.
Gill MA, Blanco P, Arce E, Pascual V, Banchereau J, Palucka AK: Blood dendritic cells and DC-poietins in systemic lupus erythematosus. Hum Immunol. 2002, 63: 1172-1180. 10.1016/S0198-8859(02)00756-5.
Scheinecker C, Zwolfer B, Koller M, Manner G, Smolen JS: Alterations of dendritic cells in systemic lupus erythematosus: phenotypic and functional deficiencies. Arthritis Rheum. 2001, 44: 856-865. 10.1002/1529-0131(200104)44:4<856::AID-ANR142>3.3.CO;2-1.
Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J: Induction of dendritic cell differentiation by IFN-alpha in systemic lupus erythematosus. Science. 2001, 294: 1540-1543. 10.1126/science.1064890.
Gary-Gouy H, Lebon P, Dalloul AH: Type I interferon production by plasmacytoid dendritic cells and monocytes is triggered by viruses, but the level of production is controlled by distinct cytokines. J Interferon Cytokine Res. 2002, 22: 653-659. 10.1089/10799900260100132.
Ishikawa S, Nagai S, Sato T, Akadegawa K, Yoneyama H, Zhang YY, Onai N, Matsushima K: Increased circulating CD11b+CD11c+ dendritic cells (DC) in aged BWF1 mice which can be matured by TNF-alpha into BLC/CXCL13-producing DC. Eur J Immunol. 2002, 32: 1881-1887. 10.1002/1521-4141(200207)32:7<1881::AID-IMMU1881>3.0.CO;2-Z.
Heller RA, Song K, Fan N, Chang DJ: The p70 tumor necrosis factor receptor mediates cytotoxicity. Cell. 1992, 70: 47-56. 10.1016/0092-8674(92)90532-H.
Chan FK, Siegel RM, Lenardo MJ: Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity. 2000, 13: 419-422. 10.1016/S1074-7613(00)00041-8.
Karin M, Lin A: NF-kappaB at the crossroads of life and death. Nat Immunol. 2002, 3: 221-227. 10.1038/ni0302-221.
Chen G, Goeddel DV: TNF-R1 signaling: a beautiful pathway. Science. 2002, 296: 1634-1635. 10.1126/science.1071924.
Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS: NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998, 281: 1680-1683. 10.1126/science.281.5383.1680.
Micheau O, Lens S, Gaide O, Alevizopoulos K, Tschopp J: NF-kappaB signals induce the expression of c-FLIP. Mol Cell Biol. 2001, 21: 5299-5305. 10.1128/MCB.21.16.5299-5305.2001.
Wu XC, Asselin E, Tsang BK: Nuclear factor kappaB-mediated induction of Flice-like inhibitory protein prevents tumor necrosis factor alpha-induced apoptosis in rat granulosa cells. Biol Reprod. 2002, 67: 436-441.
Ohshima S, Mima T, Sasai M, Nishioka K, Shimizu M, Murata N, Yoshikawa H, Nakanishi K, Suemura M, McCloskey RV, Kishimoto T, Saeki Y: Tumour necrosis factor alpha (TNF-alpha) interferes with Fas-mediated apoptotic cell death on rheumatoid arthritis (RA) synovial cells: a possible mechanism of rheumatoid synovial hyperplasia and a clinical benefit of anti-TNF-alpha therapy for RA. Cytokine. 2000, 12: 281-288. 10.1006/cyto.1999.0552.
Yamasaki S, Kawakami A, Nakashima T, Nakamura H, Kamachi M, Honda S, Hirai Y, Hida A, Ida H, Migita K, Kawabe Y, Koji T, Furuichi I, Aoyagi T, Eguchi K: Importance of NF-kappaB in rheumatoid synovial tissues: in situ NF-kappaB expression and in vitro study using cultured synovial cells. Ann Rheum Dis. 2001, 60: 678-684. 10.1136/ard.60.7.678.
Schett G, Steiner CW, Groger M, Winkler S, Graninger W, Smolen J, Xu Q, Steiner G: Activation of Fas inhibits heat-induced activation of HSF1 and up-regulation of hsp70. FASEB J. 1999, 13: 833-842.
Graninger WB, Steiner CW, Graninger MT, Aringer M, Smolen JS: Cytokine regulation of apoptosis and Bcl-2 expression in lymphocytes of patients with systemic lupus erythematosus. Cell Death Diff. 2000, 7: 966-972. 10.1038/sj.cdd.4400724.
Watanabe-Fukunaga R, Brannan CI, Copeland NG, Jenkins NA, Nagata S: Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 1992, 356: 314-317. 10.1038/356314a0.
Takahashi T, Tanaka M, Brannan CI, Jenkins NA, Copeland NG, Suda T, Nagata S: Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell. 1994, 76: 969-976. 10.1016/0092-8674(94)90375-1.
Korner H, Cretney E, Wilhelm P, Kelly JM, Rollinghoff M, Sedgwick JD, Smyth MJ: Tumor necrosis factor sustains the generalized lymphoproliferative disorder (gld) phenotype. J Exp Med. 2000, 191: 89-96. 10.1084/jem.191.1.89.
Andreakos ET, Foxwell BM, Brennan FM, Maini RN, Feldmann M: Cytokines and anti-cytokine biologicals in autoimmunity: present and future. Cytokine Growth Factor Rev. 2002, 13: 299-313. 10.1016/S1359-6101(02)00018-7.
Boswell JM, Yui MA, Burt DW, Kelley VE: Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis. J Immunol. 1988, 141: 3050-3054.
Yokoyama H, Kreft B, Kelley VR: Biphasic increase in circulating and renal TNF-alpha in MRL-lpr mice with differing regulatory mechanisms. Kidney Int. 1995, 47: 122-130.
Tsai CY, Wu TH, Huang SF, Sun KH, Hsieh SC, Han SH, Yu HS, Yu CL: Abnormal splenic and thymic IL-4 and TNF-alpha expression in MRL-lpr/lpr mice. Scand J Immunol. 1995, 41: 157-163.
Deguchi Y, Kishimoto S: Tumour necrosis factor/cachectin plays a key role in autoimmune pulmonary inflammation in lupus-prone mice. Clin Exp Immunol. 1991, 85: 392-395.
Edwards CK, Zhou T, Zhang J, Baker TJ, De M, Long RE, Borcherding DR, Bowlin TL, Bluethmann H, Mountz JD: 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.
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. 10.1002/1529-0131(199801)41:1<139::AID-ART17>3.3.CO;2-K.
Segal R, Dayan M, Zinger H, Mozes E: Suppression of experimental systemic lupus erythematosus (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxiphylline. Lupus. 2001, 10: 23-31. 10.1191/096120301675275538.
Brennan DC, Yui MA, Wuthrich RP, Kelley VE: Tumor necrosis factor and IL-1 in New Zealand Black/White mice. Enhanced gene expression and acceleration of renal injury. J Immunol. 1989, 143: 3470-3475.
Nakamura T, Ebihara I, Fukui M, Osada S, Tomino Y, Masaki T, Goto K, Furuichi Y, Koide H: Renal expression of mRNAs for endothelin-1, endothelin-3 and endothelin receptors in NZB/W F1 mice. Ren Physiol Biochem. 1993, 16: 233-243.
Debets JM, Van der Linden CJ, Dieteren IE, Leeuwenberg JF, Buurman WA: Fc-receptor cross-linking induces rapid secretion of tumor necrosis factor (cachectin) by human peripheral blood monocytes. J Immunol. 1988, 141: 1197-1201.
Takemura T, Yoshioka K, Murakami K, Akano N, Okada M, Aya N, Maki S: Cellular localization of inflammatory cytokines in human glomerulonephritis. Virchows Arch. 1994, 424: 459-464. 10.1007/BF00191429.
Malide D, Russo P, Bendayan M: Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. Hum Pathol. 1995, 26: 558-564. 10.1016/0046-8177(95)90253-8.
Herrera-Esparza R, Barbosa-Cisneros O, Villalobos-Hurtado R, Avalos-Diaz E: Renal expression of IL-6 and TNFalpha genes in lupus nephritis. Lupus. 1998, 7: 154-158. 10.1191/096120398678919949.
Aringer M, Zimmermann C, Graninger WB, Petera P, Steiner G, Ulrich W, Smolen JS: TNF is an essential mediator in lupus nephritis. Arthritis Rheum. 2002, 46: 3418-3419.
Horai R, Saijo S, Tanioka H, Nakae S, Sudo K, Okahara A, Ikuse T, Asano M, Iwakura Y: Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J Exp Med. 2000, 191: 313-320. 10.1084/jem.191.2.313.
JS is an occasional consultant for Centocor.