Abstract
IntroductionInterleukin (IL)-36α 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-36α and its antagonist IL-36Ra are expressed in synovial tissue of arthritis patients. Furthermore, IL-36α induces MAP-kinase and NFκB signaling in human synovial fibroblasts with subsequent expression and secretion of pro-inflammatory cytokines.MethodsTo understand the pathomechanism of IL-36 dependent inflammation, we investigated the biological impact of IL-36α signaling in the hTNFtg mouse. Also the impact on osteoclastogenesis by IL-36α was tested in murine and human osteoclast assays.ResultsDiseased mice showed an increased expression of IL-36R and IL-36α 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.ConclusionThus we conclude that IL-36α does not affect the development of inflammatory arthritis.
Highlights
Interleukin (IL)-36a is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis
IL-36Ra has a 52% similarity with IL1Ra [1]. These ligands bind to the same receptor, the IL-36 receptor (IL-36R), which subsequently recruits the IL-1 receptor accessory protein (IL-1RAcP) forming a heterodimeric signaling complex, the latter is used by IL-1a and IL-1b
We examined the expression of IL-36R, IL-36a and IL-36Ra mRNA in normal and inflamed knee joints using quantitative real-time PCR
Summary
Interleukin (IL)-36a is a newly described member of the IL-1 cytokine family with a known inflammatory and pathogenic function in psoriasis. The functional deletion of the antagonist leads to severe generalized psoriasis in humans [4] This inflammatory phenotype was seen in murine models overexpressing IL-36a in basal keratinocytes which develop age-dependent inflammatory skin lesions with features of human psoriasis like acanthosis, hyperkeratosis, inflammatory cell infiltrates and enhanced cytokine production [3]. In this mouse model, IL-36a enhances the production of proinflammatory cytokines IL-17A, IL-23p19 and TNF-a in skin inflammation, cytokines which are involved in rheumatoid arthritis [5]. Stimulation with its ligands induced the production of IL-12, IL-1b, IL-6, TNF-a and IL-23 in BMDCs, while stimulated CD4+ T cells produced IFN-c, IL-4 and IL-17 [7]
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