Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation

Rheumatology (Oxford). 2016 Dec;55(12):2220-2229. doi: 10.1093/rheumatology/kew325. Epub 2016 Aug 26.


Objectives: The IL-1 family member IL-37 was recently characterized as a fundamental inhibitor of innate inflammation. We investigated the effects of recombinant IL-37 in joint inflammation and joint pathology in a mouse model of arthritis. In addition, we explored the potential for therapeutic use in human joint inflammation.

Methods: Wild-type mice were treated systemically with a recombinant form of the naturally occurring human IL-37, and then the knee joints were injected with streptococcal cell wall fragments; joint inflammation, synovial cytokine concentrations and histology were evaluated after 24 h. Mice deficient in the IL-1 family decoy receptor IL-1R8 were treated in a similar manner. The effects of IL-37 treatment were also assessed in a model of streptococcal cell wall-induced systemic inflammation. Changes in IL37 and IL1R8 gene expression were evaluated in the synovia of patients with rheumatoid arthritis.

Results: In wild-type mice, low doses (40 µg/kg) of IL-37 suppressed joint inflammation by 51.7% (P < 0.001) and significantly decreased synovial IL-1β by 84%, IL-6 by 73%, TNF-α by 33%, chemokine (C-X-C motif) ligand 1 by 58%, Chemokine (C-C motif) ligand 3 or macrophage inflammatory protein 1-alpha by 64%, IL-1α by 40% and MPO by 60%. These reductions were associated with a lower recruitment of neutrophils into the joint. The anti-inflammatory properties of IL-37 were dependent on the presence of IL-1R8, also in streptococcal cell wall-induced peritonitis. We found that gene expression of IL1R8, but not IL37, is markedly increased in the synovia of patients with rheumatoid arthritis.

Conclusion: IL-37 emerges as a key suppressor of joint and systemic inflammation. These findings indicate a rationale for using recombinant IL-37 in the treatment of arthritis.

Keywords: IL-1β; TNF-α; chemokines; cytokine; immunotherapy; neutrophils; rheumatoid arthritis.

MeSH terms

  • Animals
  • Antirheumatic Agents / pharmacology*
  • Arthritis, Experimental / drug therapy*
  • Cell Wall
  • Cytokines / metabolism
  • Humans
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology*
  • Interleukin-18 Receptor alpha Subunit / metabolism
  • Male
  • Mice, Inbred C57BL
  • Peritonitis / drug therapy
  • Recombinant Proteins / pharmacology
  • Streptococcus
  • Synovial Membrane / chemistry
  • Synovitis / drug therapy


  • Antirheumatic Agents
  • Cytokines
  • IL37 protein, human
  • Il18r1 protein, mouse
  • Interleukin-1
  • Interleukin-18 Receptor alpha Subunit
  • Recombinant Proteins