IL-36γ in enthesitis-related juvenile idiopathic arthritis and its association with disease activity

IL-36 has been implicated in the pathogenesis of spondyloarthropathies (SpA) like psoriasis and inflammatory bowel disease. Enthesitis-related arthritis (ERA) category of juvenile idiopathic arthritis is a form of juvenile SpA, however, no data is available on the role of IL-36 in this disease. IL-36 alpha, beta, gamma and IL-36R mRNA expression in blood and synovial fluid mononuclear cells and IL-36 alpha, gamma, IL-36Ra, IL-6, and IL-17 levels were measured in serum and synovial fluid (SF). IL-36 gamma production by fibroblast-like synoviocytes (FLS) upon stimulation with pro-inflammatory cytokines and its effect on FLS were also studied. mRNA levels of IL-36 alpha, IL-36 gamma, and IL-36R were increased in PBMCs of ERA patients as compared to healthy controls however only IL-36 gamma was measurable in the serum of one-third of patients. In SFMCs, all four mRNA were detectable but were lower than RA patients. SF IL-36 gamma levels correlated with disease activity score (r = 0.51, P < 0.0001), SF IL-6 (r = 0.4, P = 0.0063) and IL-17 levels (r = 0.57, P = 0.0018). Pro-inflammatory cytokines increased the expression of IL-36 gamma and IL-6 in FLS cultures. SFs from five ERA patients also increased expressions of IL-36 gamma and IL-6 in FLS which could be blocked by using IL-36Ra. This suggests that pro-inflammatory cytokines aid in the upregulation of IL-36 gamma which in turn may upregulate the expression of IL-6. This might lead to a positive feedback loop of inflammation in ERA. Association of SF levels of IL-36 gamma with disease activity further supports this possibility. IL-36Ra based therapy may have a role in ERA.