title: Treating experimental arthritis with the innate immune inhibitor interleukin-37 reduces joint and systemic inflammation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Medicine, University of Colorado Denver, Aurora, CO, USA cavalli.giulio@gmail.com.|Internal Medicine and Clinical Immunology, Vita-Salute San Raffaele University, Milan, Italy.|Department of Internal Medicine.
authors: Giulio
authors: G
authors: Cavalli
authors: Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors: Marije
authors: M
authors: Koenders
authors: R&D Systems, BioTechne, Inc., Minneapolis, MN.
authors: Vassili
authors: V
authors: Kalabokis
authors: Translational Bioinformatics, Division of Medical Oncology, University of Colorado Denver, Aurora, CO, USA.
authors: Jihye
authors: J
authors: Kim
authors: Translational Bioinformatics, Division of Medical Oncology, University of Colorado Denver, Aurora, CO, USA.
authors: Aik Choon
authors: AC
authors: Tan
authors: Research Institute Humanitas, Experimental Immunopathology Lab, Rozzano, Italy.
authors: Cecilia
authors: C
authors: Garlanda
authors: Research Institute Humanitas, Experimental Immunopathology Lab, Rozzano, Italy.
authors: Alberto
authors: A
authors: Mantovani
authors: Internal Medicine and Clinical Immunology, Vita-Salute San Raffaele University, Milan, Italy.
authors: Lorenzo
authors: L
authors: Dagna
authors: Department of Internal Medicine.
authors: Leo A B
authors: LA
authors: Joosten
authors: Department of Medicine, University of Colorado Denver, Aurora, CO, USA.|Department of Internal Medicine.
authors: Charles A
authors: CA
authors: Dinarello
mesh_terms: D000818:Animals; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002473:Cell Wall; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism / Q000494:pharmacology*; D053727:Interleukin-18 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000188:drug therapy; D011994:Recombinant Proteins / Q000494:pharmacology; D013291:Streptococcus; D013583:Synovial Membrane / Q000737:chemistry; D013585:Synovitis / Q000188:drug therapy
chemical_list: D018501:Antirheumatic Agents; D016207:Cytokines; C508587:IL37 protein, human; C508573:Il18r1 protein, mouse; D007375:Interleukin-1; D053727:Interleukin-18 Receptor alpha Subunit; D011994:Recombinant Proteins
keywords: IL-1β; TNF-α; chemokines; cytokine; immunotherapy; neutrophils; rheumatoid arthritis