المؤلفون: Koenders, Marije I, Marijnissen, Renoud J, Abdollahi-Roodsaz, Shahla, Nickerson-Nutter, Cheryl, van de Loo, Fons A, van den Berg, Wim B

المصدر: Annals of the Rheumatic Diseases; Mar2011 Supp, Vol. 70, pA52-A52, 1p

مستخلص: Objectives Interleukin-21 (IL-21) is a pleiotropic cytokine that is produced mainly by activated CD4 Th17 cells. The purpose of this study was to investigate the role of IL-21 in joint pathology during chronic experimental arthritis, in particular the effect of IL-21 receptor (IL-21R) deficiency on innate and adaptive immune responses in vivo. Methods IL-21R−/− mice and their wild-type (WT) controls were used for this study, and two experimental arthritis models were induced: chronic streptococcal cell wall (SCW) induced arthritis and antigen-induced arthritis (AIA). Results At day 28 of SCW arthritis, histological analysis of the knee joints showed significantly reduced inflammation in IL-21R−/− mice compared to their WT controls. These IL-21R−/− mice also demonstrated suppressed serum levels of IL-6, but interestingly this proinflammatory cytokine tended to be increased in the local patella-washouts. This increased local activation in IL-21R−/− mice was studied in more detail in the early phase of SCW-arthritis. Before onset and 4 days after the first intra-articular injection with SCW fragments, the expression level of various receptors and regulators was determined by QPCR. No differences were found in the expression of TLR2 and NOD2, both crucial for a response to the injected SCW fragments. However, while the WT controls showed a massive upregulation of SOCS1/3 at day 4 of arthritis, IL-21R−/− mice were significantly less capable in upregulating these genes. This failure to upregulate SOCS expression in the joint resulted in increased local expression of inflammation and destruction markers in IL-21R-deficient mice, probably due to disturbed negative regulation of cytokine and TLR signaling pathways. Interestingly, despite the increased local activation in the IL-21R−/− mice, detailed histological analysis of the joints at day 28 of the chronic SCW-arthritis demonstrated that IL-21R-deficiency protected against cartilage proteoglycan depletion and chondrocyte death. FACS analysis of synovial cells showed a significant reduction of the percentage IL-17 T cells. These findings were confirmed in a second model of chronic destructive arthritis, the mBSA-induced AIA. Also in this model, IL-21R-deficiency resulted in a significant reduction of joint inflammation and destruction compared to wild-type controls, again in striking contrast to the local increase in cytokine expression, but accompanied by suppressed numbers of Th17 cells. Conclusion Despite the local suppressive role of IL-21 via SOCS regulation, IL-21 has a more dominant prodestructive role driving Th17 cells and cartilage and bone pathology during chronic experimental arthritis. However, this dual role makes IL-21 a complicated target in the treatment of rheumatoid arthritis. [ABSTRACT FROM PUBLISHER]

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المؤلفون: Marijnissen, Renoud J, Koenders, Marije I, Smeets, Ruben L, Stappers, Mark HT, Nickerson-Nutter, Cheryl, Joosten, Leo AB, Boots, Annemieke MH, van den Berg, Wim B

المصدر: Annals of the Rheumatic Diseases; Mar2011 Supp, Vol. 70, pA51-A52, 1p

مستخلص: Background Interleukin (IL)-22 is commonly regarded as a mediator in antimicrobial responses as well as a mediator in inflammatory autoimmune diseases. Although IL-22 and IL-22R have been identified in the inflamed synovium of rheumatoid arthritis patients, the source of IL-22 and contribution to disease pathogenicity remains to be established. Material and methods The production of IL-22 by T helper cells was assessed. Naive murine T cells were cultured in vitro under Th1, Th2, iTreg and Th17 polarising conditions. Cytokines were measured in the culture supernatants, and effect on differentiation was analysed by flowcytometry. In addition, the in vivo role of IL-22 was investigated in the spontaneous arthritic IL-1Ra−/− mice. Inflamed ankle synovia were isolated and mRNA levels of IL-22 and IL-22R were quantified. IL-1Ra−/− mice were treated with neutralising anti-IL-22 antibodies. Furthermore, synovial cells were isolated and sorted into (CD3, CD19 and CD11b) fractions and analysed for cytokine production. Results In vitro tests showed that Th17 differentiated T cells produce high IL-22 levels after IL-1 and IL-23 stimulation. Interestingly, the authors found a synergistic increase in the IL-22 production after combining IL-1 and IL-23. During long-term cultures, this synergy of IL-1 and IL-23 on the IL-22 production remained, but the balance shifted towards a more prominent role for IL-23. In vivo, IL-17 was upregulated in mildly and severely inflamed tissue, while IL-22 and IL-22R were merely upregulated in severely inflamed synovia. Anti-IL-22 treatment of IL-1Ra−/− mice significantly reduced inflammation and bone erosion, suggesting an important role of IL-22 in IL-1-driven joint destruction. Isolating single cells from the inflamed synovia revealed that IL-22 was mainly produced by T cells. Furthermore, most IL-22 positive T cells co-expressed IL-17 and were increased in the severely inflamed. The cellular data confirm the involvement of Th17 cells in early and late phases of arthritis whereas the involvement of IL-22 by Th17 cells becomes manifest in the later phase of arthritis. Conclusions IL-22 expression is elevated during early phase of Th17 differentiation caused by IL-1 or IL-23 alone and in synergy. Moreover, a temporal role of IL-22 induction was found for both cytokines. Neutralising IL-22 during experimental arthritis protects against severe joint pathology, revealing an important role for IL-22 during chronic synovial inflammation. IL-17IL-22 T cells were found to be te main IL-22 producers. [ABSTRACT FROM PUBLISHER]

: Copyright of Annals of the Rheumatic Diseases is the property of BMJ Publishing Group and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)