Background/Purpose: Interleukin-37 (IL-37) is a recently identified cytokine with potent anti-inflammatory and immunosuppressive functions. This cytokine has been shown to be expressed in synovial tissue of patients with rheumatoid arthritis (RA) as well as osteoarthritis (OA), and plasma levels of IL-37 in RA have been correlated with TNF, IL-17, and disease activity during DMARD treatment. The objective of this study was to investigate the therapeutic potential of IL-37 in various mouse models and stages of experimental arthritis.

Methods: Mice transgenic for human IL-37 (IL-37tg) were generated on a C57Bl/6 background and antigen-induced arthritis (AIA) was elicited by two immunizations with methylated bovine serum albumin (mBSA) as an antigen in Freund’s complete adjuvant, and subsequently intra-articular injection with mBSA. This mono-arthritis was studied by ^99mTechnetium measurements to detect joint swelling in the arthritic knee joint, and synovial washouts were collected to assess cytokine and chemokine production by Luminex. Second, recombinant IL-37 protein was administered either prophylactic or therapeutic during collagen-induced arthritis (CIA) in DBA-1J mice (1ug/mouse/day i.p. for 2 weeks), and arthritis development was scored macroscopically three times per week. In addition, joints were collected for radiographic and histological analysis.

Results: Mice transgenic for human IL-37 demonstrated suppressed joint swelling compared to C57Bl/6 control mice early after AIA induction. In addition, these IL-37tg mice had reduced synovial levels of IL-6 and KC compared to wild-type controls, and showed a trend towards suppressed IL-17. In line with this protective effect of IL-37, exogenous recombinant IL-37 administered before onset of collagen-induced arthritis resulted in significant protective effects on the macroscopic clinical scores, although these effects were not observed on radiographic analysis. Luminex to detect serum cytokine levels demonstrated an 80% reduction in systemic IL-6 levels, while anti-TNF treatment only caused a 50% suppression. In addition, serum levels of KC seemed to be slightly reduced (P=0.06). In contrast, a therapeutic approach with exogenous IL-37 after the onset of CIA did not have any beneficial effects on further disease progression, suggesting that the therapeutic window of IL-37 treatment in arthritis is limited to new-onset or early arthritis.

Conclusion: This study is the first to show that the anti-inflammatory effect of IL-37 during experimental arthritis is limited to new-onset disease, and that IL-37 is not capable to block arthritis progression during an existing inflammation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/interleukin-37-prevents-new-onset-joint-inflammation-but-does-not-inhibit-existing-experimental-arthritis/