Blockade of IL-36 Receptor Signaling Does Not Prevent from TNF-Induced Arthritis

Introduction: Interleukin (IL)-36 alpha is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. Recently, we could demonstrate that the receptor (IL-36R), its ligand IL-36 alpha and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36 alpha induces MAP-kinase and NF kappa B signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines. Methods: To understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36 alpha signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36 alpha was tested in murine and human osteoclast assays. Results: Diseased mice showed an increased expression of IL-36R and IL-36 alpha in inflamed knee joints compared to wildtype controls. However, preventively treating mice with an IL-36R blocking antibody led to no changes in clinical onset and pattern of disease. Furthermore, blockade of IL-36 signaling did not change histological signs of TNF-induced arthritis. Additionally, no alteration on bone homeostasis was observed in ex vivo murine and human osteoclast differentiation assays. Conclusion: Thus we conclude that IL-36 alpha does not affect the development of inflammatory arthritis.