Reduction of urate crystal-induced inflammation by root extracts from traditional oriental medicinal plants: elevation of prostaglandin D2levels
© Jung et al.; licensee BioMed Central Ltd. 2007
Received: 05 February 2007
Accepted: 05 July 2007
Published: 05 July 2007
Dried roots of the plants Acanthopanax senticosus, Angelica sinensis and Scutellaria baicalensis are used in traditional oriental medicine and reportedly possess anti-inflammatory properties. Using the murine air pouch model of inflammation, we investigated the efficacy and mode of action of an extract from these three plants in crystal-induced inflammation. Air pouches were raised on the backs of 8-week-old BALB/c mice. Mice were fed 100 mg/kg body weight of root extracts (A. senticosus:A. sinensis:S. baicalensis mixed in a ratio of 5:4:1 by weight) or vehicle only on days 3–6. Inflammation was elicited on day 6 by injecting 2 mg of monosodium urate (MSU) crystals into the pouch. Neutrophil density and IL-6 and TNF-α mRNA levels were determined in the pouch membrane, and the leukocyte count and IL-6, prostaglandin E2 (PGE2) and prostaglandin D2 (PGD2) levels were determined in the pouch exudate. Treatment with the root extracts led to a reduction in all inflammatory parameters: the leukocyte count in the pouch exudate decreased by 82%; the neutrophil density in the pouch membrane decreased by 68%; IL-6 and TNF-α mRNA levels in the pouch membrane decreased by 100%; the IL-6 concentration in the pouch fluid decreased by 50%; and the PGE2 concentration in the pouch fluid decreased by 69%. Remarkably, the concentration of the potentially anti-inflammatory PGD2 rose 5.2-fold in the pouch exudate (p < 0.005), which led to a normalization of the PGD2:PGE2 ratio. A 3.7-fold rise in hematopoietic PGD synthase (h-PGDS) mRNA paralleled this rise in PGD2 (p = 0.01).
Thus, the root extracts diminished MSU crystal-induced inflammation by reducing neutrophil recruitment and expression of pro-inflammatory factors and increasing the level of the potentially anti-inflammatory PGD2. These results support a need for further studies of the efficacy of these extracts in the treatment of inflammatory arthropathies and suggest elevation of PGD2 levels as a novel mechanism for an anti-inflammatory agent.
Powderized dried roots of the plants Acanthopanax senticosus (Siberian ginseng), Angelica sinensis (Dong Quai) and Scutellaria baicalensis (Baikal Skullcap) are commonly used in oriental medicine for a variety of indications based on traditional concepts. A. senticosus is used as a general tonic to stimulate Qi forces . A. sinensis is used, for instance, to treat blood deficiency with wind–damp painful obstruction [2, 3], and S. baicalensis is used to clear heat, remove toxins and restrain bleeding [4, 5]. All three plants are contained in herbal mixtures used for the treatment of chronic inflammatory disorders, including arthritis . Pharmacologic studies in animals have documented the anti-inflammatory effects of all three plants. A. senticosus has been shown to reduce the expression of cyclo-oxygenase (COX)-2 and complement type 3 receptor (a marker for microglia in the central nervous system) in cerebral ischemia  and to inhibit mast cell-dependent anaphylaxis . A. sinensis root polysaccharides inhibited neutrophil migration in ethanol-induced gastrointestinal inflammation in rats  and reduced expression of pro-inflammatory factors in experimental colitis in rats . The flavonoids baicalein, which binds to chemokine ligands and inhibits leukotriene C4 synthesis, and wogonin have been implicated as the principal anti-inflammatory active ingredients of S. baicalensis [11, 12].
Considering their anti-inflammatory properties, extracts or mixtures of extracts from these plants might be suitable for the treatment or prevention of inflammatory arthropathies. Mixtures of medicinal herbs containing root preparations from these three herbs are indeed used in traditional oriental medicine for this purpose , and there is anecdotal evidence from clinical experience in traditional oriental medicine that these herbs might be effective in treating musculoskeletal pain and arthritis (H.C. Kim, S.M. Jung, unpublished data). However, these herbs have not been validated for the treatment of acute or chronic synovitis in clinical studies or animal models of arthritis. As a first step, we therefore wanted to investigate the efficacy and mode of action of a mixture of standardized root extracts from the three plants in a simple animal model that resembles acute synovitis in humans.
The murine air pouch model represents an easily manipulable animal model of acute inflammation that has been used extensively in studies of a variety of anti-inflammatory agents. In contrast to animal models of chronic arthritis, the murine air pouch model lends itself well to the study of orally administered agents because it does not require prolonged gavage feedings of test substances to the animals. The air pouch is a newly formed, bursa-like tissue that grows around subcutaneously injected air and resembles the human synovial lining . For the purposes of definition, we shall refer to this newly formed tissue as the 'pouch membrane'. Depending on the pro-inflammatory agent instilled into the pouch, distinct forms of inflammation can be elicited . Injection of monosodium urate (MSU) crystals results in transient neutrophilic inflammation that resembles acute gouty arthritis in humans [15, 16] and induces major pro-inflammatory cytokines that are active in chronic inflammatory arthropathies, such as TNF-α and IL-1 and -6 [17–19]. Here, we show that the root extracts strongly inhibit inflammation in this model by decreasing neutrophil immigration into the pouch membrane, reducing expression of pro-inflammatory factors, including prostaglandin E2 (PGE2), and raising the level of the potentially anti-inflammatory prostaglandin D2 (PGD2), thereby normalizing the PGD2:PGE2 ratio. These findings suggest elevation of PGD2 levels as a novel mechanism of action for an anti-inflammatory agent.
Materials and methods
RNA extraction and analysis of gene expression
Sequences of PCR primers used
Histology and immunohistochemistry
Full-thickness tissue pieces, containing skin and pouch membrane and measuring approximately 2 × 2 cm, were excised from the lateral aspects of the pouch (the same location was used in all cases). They were then fixed in formalin for 24–48 hours, embedded in paraffin and sectioned. H&E stains were performed according to standard laboratory procedures. The neutrophil density was counted independently by two observers (S.M. Jung, F. Pessler) in one section from each of two tissue pieces per animal. As recommended previously , five representative high-power fields (× 600 magnification), containing intact pouch membrane and adjacent subcutaneous tissues, were evaluated per section. Fields containing large blood vessels or follicular inflammatory aggregates were excluded. In all analyses, statistical significance was determined using the Student's t test.
Treatment with the root extracts
Authentication of the extracts by HPLC
Final concentration of compound used for standardization (mg/100 g)
Eleutheroside B, 0.081
Eleutheroside D, 0.44
Freeze-dried plant extracts were combined (A. senticosus:A. sinensis:S. baicalensis in a ratio of 5:4:1 by weight) and then dissolved in distilled water, to a final concentration of 2 mg/ml. These proportions were chosen according to previous preliminary results in a mouse model of cerebral reperfusion injury, which has a strong inflammatory component (H. Kim, unpublished data). Using a 22-gauge, 1.5-inch rigid feeding tube (Ejay International, Glendora, CA, USA) mice were gavage-fed 1 ml of this solution (corresponding to 100 mg of freeze-dried extracts/kg body weight) or 1 ml of water once daily, as outlined in Figure 1. There were no deaths or illnesses among the mice.
Validating the time of maximal inflammation in this model
The leukocyte count of the pouch exudate is the commonly used end point in the air pouch model. A time-course experiment showed that the leukocyte density of the pouch exudate peaked 9 hours after instillation of MSU crystals and then subsided gradually over the following 27 hours (Figure 1b). The 9-hour time point, which reflected a 24-fold increase in the leukocyte count of the exudate, was thus chosen for all subsequent experiments.
Reduction of inflammation and inflammatory mediators by treatment with the root extracts
Summary of effects of the root extracts*
No. of mice per group
Leukocyte count, exudate
Neutrophil density, membrane
IL-6 protein, exudate
IL-6 mRNA, membrane
4 + 4**
TNF-α mRNA, membrane
4 + 4**
Ratio of PGD2:PGE2
h-PGDS mRNA, membrane
Increase in the level of prostaglandin D2by treatment with the root extracts
PGD2 is a pleiotropic prostaglandin that has been associated with anti-inflammatory properties and the resolution of inflammation [24, 25], and it is the precursor of the anti-inflammatory prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2) . We hypothesized that the root mixture might function partially by increasing the level of this potentially anti-inflammatory substance. At the 9-hour time point, a modest rise in the PGD2 level was seen in the MSU-treated pouches (Figure 4e), potentially heralding initiation of the natural resolution phase of inflammation. Strikingly, treatment with the root extracts resulted in a 5.2-fold augmentation of this small increase in the level of PGD2 in the pouch exudate (p < 0.005 (t test); Figure 4e). The simultaneous decrease in PGE2 and increase in PGD2 levels induced by the extracts normalized the PGD2:PGE2 ratio, which increased ninefold and was now slightly higher than that in the control group (Figure 4e and Table 3). To assess whether the increase in the level of PGD2 was, at least in part, owing to increased expression of h-PGDS (the enzyme responsible for PGD2 synthesis outside the nervous system), we measured h-PGDS mRNA levels in the pouch membrane by real-time RT-PCR. Indeed, treatment with the root extracts led to a 3.7-fold increase (p = 0.001 (t test)) in h-PGDS mRNA compared with MSU crystal-stimulated pouches from mice not receiving the root extracts (Table 3).
A mixture of root extracts from A. senticosus, A. sinensis and S. baicalensis demonstrated strong anti-inflammatory properties in this model of MSU crystal-induced neutrophilic inflammation. These results agree well with previous reports that each herb exhibited some form of anti-inflammatory property in other experimental models.
The mode of action of this mixture seems to be owing to both a reduction of pro-inflammatory factors and a stimulation of at least one potentially anti-inflammatory factor, PGD2. TNF-α, IL-6 and PGE2 all have important roles in inflammatory arthropathies, including gout [26–28]. Moreover, the levels PGE2 and TNF-α are elevated in the inflamed rat air pouch , and, in preliminary studies of the microarray analysis of isolated murine air pouch membranes stimulated with MSU crystals, we have recently identified IL-6 as an MSU crystal-induced cytokine in the air pouch membrane and localized its expression to membrane fibroblasts and inflammatory cells . Reductions in the levels of all these pro-inflammatory factors paralleled the reduction of the leukocyte count in the pouch exudate of mice treated with the root extracts. A reduction in neutrophil numbers within the pouch membrane was also observed, proving that the root extracts inhibited neutrophil recruitment and/or migration into the pouch membrane and not just their exit into the pouch exudate. We cannot explain fully why treatment with the extracts completely prevented the rise in the level of IL-6 mRNA in the pouch membrane, whereas a reduced level of IL-6 protein was still detected in the pouch exudate. The level of IL-6 mRNA peaks in MSU-stimulated air pouch membranes 1–4 hours after MSU injection and is up to tenfold higher than the level at 9 hours (F. Pessler, S.M. Jung, H.R. Schumacher, unpublished data). It is, therefore, possible that the low level at 9 hours reflects an overall reduction of IL-6 transcription throughout the time course and that some elevation of IL-6 mRNA would still be detectable at the earlier time points in MSU-stimulated mice treated with the extracts. Considering the short half-life of IL-6 mRNA and strong role of mRNA stabilization in regulation of IL-6 expression [29, 30], another possible explanation is that the root extracts increased turnover of IL-6 mRNA, whereas the stability of the IL-6 protein was unaffected. Alternatively, active ingredients from the root extracts perhaps achieved higher concentrations in the pouch membrane than the exudate, in which leukocytes continued to synthesize IL-6. We did not test for potential effects of the extracts on IL-1β expression in the air pouch membrane. However, in ongoing investigations into the effects of the extracts on inflammatory mediator synthesis by cultured murine macrophages, we have detected a >95% reduction of MSU crystal-induced IL-1β and IL-6 mRNA synthesis (F. Pessler, H.C. Kim, H.R. Schumacher, unpublished results). It, therefore, seems probable that the extracts reduce the major pro-inflammatory cytokines nonselectively and thus do not affect any one cytokine specifically.
The effects of the extracts were assessed after four doses (feedings). This regimen was chosen because it was probably the earliest point at which steady-state serum levels of gastrointestinally absorbed substances could be expected. It will now be important to determine in greater detail the effective dose(s), time to onset of the anti-inflammatory effects and effects on established inflammation and to test other routes of administration.
The rise in the level of PGD2, the precursor of the anti-inflammatory PGJ2, following treatment with the root extracts, represents an intriguing observation. To our knowledge, elevation of PGD2 levels has not been described as the effect of an anti-inflammatory agent. Although it is also involved in acute inflammatory states, such as asthma [31, 32], PGD2 is now increasingly recognized as an important mediator of the resolution of inflammation. For instance, h-PGDS mRNA  and PGD2 levels  rise during the resolution phase of an acute inflammatory response and h-PGDS knock-out mice fail to resolve a delayed-type hypersensitivity reaction . Moreover, administration of PGD2 or its metabolite PGJ2 reduces the severity of carrageenan-induced pleurisy [34, 36]. The prophylactic anti-inflammatory properties of PGD2 have also been demonstrated in the murine air pouch . Injection of MSU crystals led to a decrease of endogenous PGD2 synthase, whereas intrapouch injection of fibroblasts overexpressing the enzyme resulted in decreased inflammation and expression of pro-inflammatory mediators. It is thus tempting to speculate that the root extracts reduced inflammation, in part, by raising the level of PGD2. The modest increase in h-PGDS mRNA argues that this might be partly owing to an elevated h-PGDS level, but other mechanisms, such as enhanced h-PGDS activity or PGD2 stability, are also plausible. It is unclear whether PGD2 itself or its degradation product PGJ2 mediates the apparent anti-inflammatory effect of the root extracts. We have been unable to detect PGJ2 in lavaged air pouch exudates by ELISA. This might be because of the instability of PGJ2 in this model  or because the PGJ2 level rises later during the resolution phase of inflammation. Interestingly, TNF-α raises PGE2, but decreases PGD2, synthesis by zymosan-stimulated murine macrophages . The normalization of the PGD2:PGE2 ratio by the root extracts paralleled the inhibition of TNF-α mRNA synthesis in the pouch membrane, thus raising the possibility that inhibition of TNF-α might be part of the mechanism for PGD2 stimulation in this model. Consistent with this hypothesis, in addition to neutrophils, monocytes and macrophages (cell types capable of high levels of TNF-α synthesis) represent the predominant inflammatory cells in the air pouch membrane. Transforming growth factor (TGF)-β is strongly associated with the resolution of crystal-induced inflammation [38, 39]. Although we did not assay TGF-β levels, it is possible that treatment with the extracts might affect levels of anti-inflammatory substances in general and thus raise the level of TGF-β in parallel with that of PGD2. It would, therefore, be interesting to measure TGF-β levels in future studies that aim to define the mechanism of action of the extracts further.
How do commonly used anti-inflammatory agents, such as NSAIDs and corticosteroids, affect PGD2 levels? In an endotoxin-based mouse model of inflammation, administration of aspirin or indomethacin nearly abolished both PGE2 and PGD2 synthesis, whereas PGD2 levels rose during the natural resolution of inflammation in untreated animals . Dexamethasone inhibited PGD2 synthesis in zymosan-stimulated murine macrophages . Prednisone did not alter PGD2 synthesis during the cutaneous late-phase allergic response in humans . It is, therefore, unlikely that NSAIDs or corticosteroids commonly function by raising the level of PGD2.
Our results do not enable us to determine whether the root extracts predominantly blunted the inflammatory response at its onset or whether they also expedited its resolution. Considering their dual effects on pro- and anti-inflammatory factors, we favor a combination of the two possibilities. As commonly practiced in traditional oriental medicine, a mixture of herbs was used. Future studies should be directed towards determining the relative contribution(s) of each herb, to assess potential synergistic effects and isolate the active ingredient(s).
A mixture of root extracts from oriental medicinal plants diminished MSU crystal-induced inflammation by reducing neutrophil recruitment and expression of pro-inflammatory factors and increasing the level of the potentially anti-inflammatory PGD2. These results suggest elevation of PGD2 levels as a novel mechanism for an anti-inflammatory agent. Preliminary data suggest that raised h-PGDS mRNA levels might be part of the mechanism underlying the elevation of PGD2 levels. These results support a need for efforts directed at the identification of the major active ingredient(s) of the extracts and for further studies of their efficacy in the treatment of inflammatory arthropathies.
= threshold cycle
= enzyme-linked immunosorbent assay
= glyceraldehyde 3-phosphate dehydrogenase
= hematoxylin and eosin
= hematopoietic prostaglandin D synthase
= high-performance liquid chromatography
= monosodium urate
= nonsteroidal anti-inflammatory drug
= phosphate-buffered saline
= prostaglandin D2
= prostaglandin E2
- PGJ2 = 15-deoxy-Δ12:
= reporter-dye signals
= reverse transcriptase polymerase chain reaction
= transforming growth factor
= tumor necrosis factor.
We thank Gilda Clayburne for technical help, Peri DeRitis and the staff of the Philadelphia Veterans Affairs Medical Center Animal Care Center (PA, USA) for their expert assistance with animal care, Dan Martinez and the staff of the Histopathology Core of the Children's Hospital of Philadelphia (PA, USA) for their assistance with histology, Robert Zurier (University of Massachusetts, Worchester, MA, USA) and Michael Heinrich (University College of London, London, UK) for helpful discussion and critical reading of earlier versions of the manuscript, and Christian Mayer for editorial assistance. These data have been submitted in partial fulfillment of the degree of Doctor of Philosophy in Herbal Pharmacology (SMJ). This project was approved by the Animal Care Committee of the Philadelphia Veterans Affairs Medical Center (PA, USA). FP was supported by National Institutes of Health Training Grants T32-AR 007442 and T32-CA 09140.
- Collisson R: Siberian ginseng. Brit J Phytother. 1991, 2: 61-71.Google Scholar
- Deyama T, Nishibe S, Nakazawa Y: Constituents and pharmacological effects of Eucommia and Siberian ginseng. Acta Pharmacol Sin. 2001, 22: 1057-1070.PubMedGoogle Scholar
- Tse TW: Use of common Chinese herbs in the treatment of psoriasis. Clin Exp Dermatol. 2003, 28: 469-475. 10.1046/j.1365-2230.2003.01322.x.View ArticlePubMedGoogle Scholar
- Kubo M, Matsuda H, Tanaka M, Kimura Y, Okuda H, Higashino M, Tani T, Namba K, Arichi S: Studies on Scutellariae radix. VII. Anti-arthritic and anti-inflammatory actions of methanolic extract and flavonoid components from Scutellariae radix. Chem Pharm Bull (Tokyo). 1984, 32: 2724-2729.View ArticleGoogle Scholar
- Newall C, Anderson LA, Phillipson JD: Herbal Medicines: A Guide for Health-Care Professionals. 1996, London: Pharmaceutical PressGoogle Scholar
- Kim H: Herbal Pharmacology [Korean]. 2001, Seoul: Jip-Moon PressGoogle Scholar
- Bu Y, Jin ZH, Park SY, Baek S, Rho S, Ha N, Park SK, Kim H: Siberian ginseng reduces infarct volume in transient focal cerebral ischaemia in Sprague-Dawley rats. Phytother Res. 2005, 19: 167-169. 10.1002/ptr.1649.View ArticlePubMedGoogle Scholar
- Shen ML, Zhai SK, Chen HL, Luo YD, Tu GR, Ou DW: Immunomopharmacological effects of polysaccharides from Acanthopanax senticosus on experimental animals. Int J Immunopharmacol. 1991, 13: 549-554.View ArticlePubMedGoogle Scholar
- Cho CH, Mei QB, Shang P, Lee SS, So HL, Guo X, Li Y: Study of the gastrointestinal protective effects of polysaccharides from Angelica sinensis in rats. Planta Med. 2000, 66: 348-351. 10.1055/s-2000-8552.View ArticlePubMedGoogle Scholar
- Liu SP, Dong WG, Wu DF, Luo HS, Yu JP: Protective effect of angelica sinensis polysaccharide on experimental immunological colon injury in rats. World J Gastroenterol. 2003, 9: 2786-2790.PubMed CentralView ArticlePubMedGoogle Scholar
- Li BQ, Fu T, Gong WH, Dunlop N, Kung H, Yan Y, Kang J, Wang JM: The flavonoid baicalin exhibits anti-inflammatory activity by binding to chemokines. Immunopharmacology. 2000, 49: 295-306. 10.1016/S0162-3109(00)00244-7.View ArticlePubMedGoogle Scholar
- Chi YS, Lim H, Park H, Kim HP: Effects of wogonin, a plant flavone from Scutellaria radix, on skin inflammation: in vivo regulation of inflammation-associated gene expression. Biochem Pharmacol. 2003, 66: 1271-1278. 10.1016/S0006-2952(03)00463-5.View ArticlePubMedGoogle Scholar
- Edwards JC, Sedgwick AD, Willoughby DA: The formation of a structure with the features of synovial lining by subcutaneous injection of air: an in vivo tissue culture system. J Pathol. 1981, 134: 147-156. 10.1002/path.1711340205.View ArticlePubMedGoogle Scholar
- Nagase M, Baker DG, Schumacher HR: Prolonged inflammatory reactions induced by artificial ceramics in the rat air pouch model. J Rheumatol. 1988, 15: 1334-1338.PubMedGoogle Scholar
- Gordon TP, Kowanko IC, James M, Roberts-Thomson PJ: Monosodium urate crystal-induced prostaglandin synthesis in the rat subcutaneous air pouch. Clin Exp Rheumatol. 1985, 3: 291-296.PubMedGoogle Scholar
- Tate GA, Mandell BF, Schumacher HR, Zurier RB: Suppression of acute inflammation by 15 methyl prostaglandin E1. Lab Invest. 1988, 59: 192-199.PubMedGoogle Scholar
- Murakami Y, Akahoshi T, Hayashi I, Endo H, Hashimoto A, Kono S, Kondo H, Kawai S, Inoue M, Kitasato H: Inhibition of monosodium urate monohydrate crystal-induced acute inflammation by retrovirally transfected prostaglandin D synthase. Arthritis Rheum. 2003, 48: 2931-2941. 10.1002/art.11271.View ArticlePubMedGoogle Scholar
- Jung S, Schumacher H, Dai L, Pessler F: Identification of pro-inflammatory genes by genomic analysis of the isolated monosodium urate-stimulated murine air pouch membrane [abstract]. Arthritis Rheum. 2005, 52: 4074-10.1002/art.20866.View ArticleGoogle Scholar
- Nalbant S, Chen LX, Sieck MS, Clayburne G, Schumacher HR: Prophylactic effect of highly selective COX-2 inhibition in acute monosodium urate crystal induced inflammation in the rat subcutaneous air pouch. J Rheumatol. 2005, 32: 1762-1764.PubMedGoogle Scholar
- McCarty DJ, Faires JS: A comparison of the duration of local anti-inflammatory effect of several adrenocorticosteroid esters – a bioassay technique. Curr Ther Res Clin Exp. 1963, 5: 284-290.PubMedGoogle Scholar
- Schumacher HR, Reginato AJ: Atlas of Synovial Fluid Analysis and Crystal Identification. 1991, Philadelphia: Lea and Fiebiger, 1Google Scholar
- ABI PRISM 7700 Sequence Detection System User Bulletin #2. [http://docs.appliedbiosystems.com/pebiodocs/04303859.pdf]
- Schiltz C, Lioté F, Prudhommeaux F, Meunier A, Champy R, Callebert J, Bardin T: Monosodium urate monohydrate crystal-induced inflammation in vivo: quantitative histomorphometric analysis of cellular events. Arthritis Rheum. 2002, 46: 1643-1650. 10.1002/art.10326.View ArticlePubMedGoogle Scholar
- Gilroy DW, Colville-Nash PR, McMaster S, Sawatzky DA, Willoughby DA, Lawrence T: Inducible cyclooxygenase-derived 15-deoxy(Delta)12-14PGJ2 brings about acute inflammatory resolution in rat pleurisy by inducing neutrophil and macrophage apoptosis. FASEB J. 2003, 17: 2269-2271.PubMedGoogle Scholar
- Lawrence T, Willoughby DA, Gilroy DW: Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol. 2002, 2: 787-795. 10.1038/nri915.View ArticlePubMedGoogle Scholar
- di Giovine FS, Malawista SE, Thornton E, Duff GW: Urate crystals stimulate production of tumor necrosis factor alpha from human blood monocytes and synovial cells. Cytokine mRNA and protein kinetics, and cellular distribution. J Clin Invest. 1991, 87: 1375-1381.PubMed CentralView ArticlePubMedGoogle Scholar
- Brozik M, Rosztoczy I, Meretey K, Balint G, Gaal M, Balogh Z, Bart M, Mituszova M, Velics V, Falus A: Interleukin 6 levels in synovial fluids of patients with different arthritides: correlation with local IgM rheumatoid factor and systemic acute phase protein production. J Rheumatol. 1992, 19: 63-68.PubMedGoogle Scholar
- Pouliot M, James MJ, McColl SR, Naccache PH, Cleland LG: Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes. Blood. 1998, 91: 1769-1776.PubMedGoogle Scholar
- Elias JA, Lentz V: IL-1 and tumor necrosis factor synergistically stimulate fibroblast IL-6 production and stabilize IL-6 messenger RNA. J Immunol. 1990, 145: 161-166.PubMedGoogle Scholar
- Le PT, Lazorick S, Whichard LP, Haynes BF, Singer KH: Regulation of cytokine production in the human thymus: epidermal growth factor and transforming growth factor alpha regulate mRNA levels of interleukin 1 alpha (IL-1 alpha), IL-1 beta, and IL-6 in human thymic epithelial cells at a post-transcriptional level. J Exp Med. 1991, 174: 1147-1157. 10.1084/jem.174.5.1147.View ArticlePubMedGoogle Scholar
- Luster AD, Tager AM: T-cell trafficking in asthma: lipid mediators grease the way. Nat Rev Immunol. 2004, 4: 711-724. 10.1038/nri1438.View ArticlePubMedGoogle Scholar
- Ulven T, Kostenis E: Targeting the prostaglandin D2 receptors DP and CRTH2 for treatment of inflammation. Curr Topics Med Chem. 2006, 6: 1427-1444.View ArticleGoogle Scholar
- Schuligoi R, Grill M, Heinemann A, Peskar BA, Amann R: Sequential induction of prostaglandin E and D synthases in inflammation. Biochem Biophys Res Commun. 2005, 335: 684-689. 10.1016/j.bbrc.2005.07.130.View ArticlePubMedGoogle Scholar
- Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA: Inducible cyclooxygenase may have anti-inflammatory properties. Nat Med. 1999, 5: 698-701. 10.1038/9550.View ArticlePubMedGoogle Scholar
- Trivedi SG, Newson J, Rajakariar R, Jacques TS, Hannon R, Kanaoka Y, Eguchi N, Colville-Nash P, Gilroy DW: Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type hypersensitivity. Proc Natl Acad Sci USA. 2006, 103: 5179-5184. 10.1073/pnas.0507175103.PubMed CentralView ArticlePubMedGoogle Scholar
- Ianaro A, Ialenti A, Maffia P, Pisano B, Di Rosa M: Role of cyclopentenone prostaglandins in rat carrageenin pleurisy. FEBS Lett. 2001, 508: 61-66. 10.1016/S0014-5793(01)03035-6.View ArticlePubMedGoogle Scholar
- Fournier T, Fadok V, Henson PM: Tumor necrosis factor-alpha inversely regulates prostaglandin D2 and prostaglandin E2 production in murine macrophages. Synergistic action of cyclic AMP on cyclooxygenase-2 expression and prostaglandin E2 synthesis. J Biol Chem. 1997, 272: 31065-31072. 10.1074/jbc.272.49.31065.View ArticlePubMedGoogle Scholar
- Lioté F, Prudhommeaux F, Schiltz C, Champy R, Herbelin A, Ortiz-Bravo E, Bardin T: Inhibition and prevention of monosodium urate monohydrate crystal-induced acute inflammation in vivo by transforming growth factor beta1. Arthritis Rheum. 1996, 39: 1192-1198. 10.1002/art.1780390718.View ArticlePubMedGoogle Scholar
- Yagnik DR, Evans BJ, Florey O, Mason JC, Landis RC, Haskard DO: Macrophage release of transforming growth factor beta1 during resolution of monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum. 2004, 50: 2273-2280. 10.1002/art.20317.View ArticlePubMedGoogle Scholar
- Charlesworth EN, Kagey-Sobotka A, Schleimer RP, Norman PS, Lichtenstein LM: Prednisone inhibits the appearance of inflammatory mediators and the influx of eosinophils and basophils associated with the cutaneous late-phase response to allergen. J Immunol. 1991, 146: 671-676.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.