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A7.04 IL-37: Therapeutic potential of a natural inhibitor of innate immunity during acute and chronic experimental arthritis
  1. MI Koenders1,
  2. G Cavelli2,
  3. LA Joosten3,
  4. PM van der Kraan1,
  5. WB van den Berg1,
  6. CA Dinarello2
  1. 1Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands
  2. 2Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA
  3. 3Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands


Background and objectives Recently characterised as a fundamental inhibitor of innate immunity and inflammation, member of the Interleukin (IL)-1 family IL-37 is highly expressed in the inflamed synovial tissue of patients with rheumatoid arthritis. We investigated the role of IL-37 in joint inflammation and the effects of IL-37 treatment on joint pathology in several mouse model of experimental arthritis.

Materials and methods A strain of Bl/6 mice transgenic for human IL-37 (IL-37tg) was generated, and acute arthritis was induced by intra-articular delivery of streptococcal cell wall (SCW)-fragments. C57Bl/6 mice were also subjected to SCW-induced arthritis, and treated with a recombinant form of the naturally occurring human IL-37. Furthermore, chronic antigen-induced arthritis (AIA) was induced in IL-37tg mice by intra-articular delivery of methylated BSA as antigen, after systemic immunisation and booster with mBSA in FCA. Subsequently, DBA-1 mice with collagen-induced arthritis were treated with IL-37 recombinant protein. Arthritis development and histopathology of the joints were our first readout parameter. In addition, cytokine expression was determined in serum and synovial tissue.

Results IL-37 gene expression in the synovium of IL-37tg mice reached peak levels in the resolution phase of acute SCW  arthritis, thus not optimally exploiting the anti-inflammatory properties of IL-37. However, exogenously administered IL-37 effectively suppressed acute joint inflammation. This protective effect was associated with a decrease in synovial and systemic pro-inflammatory mediators, and with reduced recruitment of granulocytes to the inflamed joint. In line with this protective effect, mice transgenic for human IL-37 demonstrated suppressed joint swelling compared to wild-type control mice early after AIA induction. In addition, these IL-37tg mice had reduced synovial levels of IL-6 and KC, and showed a trend towards suppressed IL-17. Furthermore, exogenously administered IL-37 effectively suppressed arthritis incidence and disease severity during collagen-induced arthritis, thereby demonstrating the protective effects of IL-37 in both acute and chronic models of experimental arthritis.

Conclusions IL-37 emerges as a key player in joint inflammation. The findings provide rationale for a protective role of IL-37 in the pathogenesis of arthritis, and imply a therapeutic potential for IL-37 administration.

  • IL-37
  • interleukins
  • cytokines
  • novel therapeutics
  • experimental arthritis

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