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Rheumatology (Oxford). 2016 Dec;55(12):2220-2229. Epub 2016 Aug 26.

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

Author information

1
Department of Medicine, University of Colorado Denver, Aurora, CO, USA cavalli.giulio@gmail.com.
2
Internal Medicine and Clinical Immunology, Vita-Salute San Raffaele University, Milan, Italy.
3
Department of Internal Medicine.
4
Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands.
5
R&D Systems, BioTechne, Inc., Minneapolis, MN.
6
Translational Bioinformatics, Division of Medical Oncology, University of Colorado Denver, Aurora, CO, USA.
7
Research Institute Humanitas, Experimental Immunopathology Lab, Rozzano, Italy.
8
Department of Medicine, University of Colorado Denver, Aurora, CO, USA.

Abstract

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

PMID:
27567100
PMCID:
PMC5144668
DOI:
10.1093/rheumatology/kew325
[Indexed for MEDLINE]
Free PMC Article

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