Background and Objectives The interleukin (IL)-36α is a recently described member of the IL-1 cytokine family with pro-inflammatory and clearly pathogenic properties in psoriasis arthritis (PsA). The majority of patients with PsA and rheumatoid arthritis (RA) benefit from cytokine blocking therapies against TNFα; however, despite novel developments, subgroups of patients do not respond to this therapy. Therefore it is necessary to get a better understanding of the pathogenesis of synovitis in PsA and RA to learn more about the complex cellular interplay and to develop new treatment approaches. Therefore, we wanted to determine the IL-36α expression in PsA compared to RA and osteoarthritis (OA).
Materials and Methods Synovial tissue obtained from arthritis patients were stained for IL-36α, IL-36 receptor (IL-36R) and IL-36R antagonist (IL-36Ra) by immunohistochemistry and immunofluorescence. Lysates were tested for IL-36α by immunoblotting. Synovial fibroblasts (FLS) cultured in the presence of IL-36α were assessed for cytokine expression by quantitative real time PCR and Multiplex assay. IL-36α-induced signal transduction in FLS was analysed by immunoblotting.
Results The IL-36R and its ligands IL-36α and IL-36Ra could be detected in inflammatory arthritis in the synovial lining layer as well as cellular infiltrates. IL-36α was significantly higher expressed in PsA and RA synovium compared to OA (p = 0.0011 and p < 0.0001, respectively). No differences were seen in IL-36R and IL-36Ra. The expression of IL-36α was confirmed by western blot analysis. IL-36α induced expression of IL-6 and IL-8 in FLS. CD138-positive plasma cells were defined as a major cellular source for IL-36α. Functionally, IL-36α induced the expression of IL-6 and IL-8 in FLS through NF-κB/p38-activation.
Conclusions Here, we describe that the novel cytokine IL-36α, mainly expressed by plasma cells, is upregulated in PsA and RA synovium and leads to IL-6 and IL-8 production by synovial fibroblasts. This finding needs further studies to determine if the IL-36 family can function as a potential target for arthritis therapy.
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