A1.16 Interleukin-36α activates fibroblast like synoviocytes. (31st January 2014)

• Record Type: Journal Article
• Authors: Kästele, Verena; Wagner, Olga; Derer, Anja; Schmitt, Verena; Schett, Georg; Frey, Silke; Hueber, Axel J
• Is Part Of: Annals of the rheumatic diseases. Volume 73:Supplement 1(2014)
• Page Start: A6
• Page End: A7
• Publication Date: 2014-01-31
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2013-205124.15
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Interleukin-36α (IL-36α) is a member of the IL-1 family and has pro-inflammatory properties. It binds to the IL-36 receptor (IL-36R) whereby the IL-1 receptor accessory protein (IL-1RacP) is recruited to form a heterodimeric receptor. In transfected cell lines this binding activates MAP-kinases and NF-κB signalling and further induces the expression of pro-inflammatory cytokines. In rheumatoid arthritis (RA) synovium IL-36α is significantly higher expressed compared to osteoarthritis (OA) synovium. Both OA and RA synovial like fibroblasts (FLS) express IL-36R and can similarly be activated through IL-36α. Objectives: To determine the role and function of IL-36α in RA, in particular the impact on FLS and how this cell activation contributes to further inflammatory responses in the pathogenesis of RA. Materials and Methods: FLS of RA and OA patients were isolated and stimulated with IL-36α to analyse intracellular signal transduction by immunoblotting. To confirm signalling pathways, FLS of WT, MK2-/- and IL-36R-/- mice were cultured with IL-36α and assessed for cytokine and MMP expression. This expression pattern was additional assayed for IL-36α-activated human FLS and was performed by quantitative real time, multiplex assay and ELISA. Further, FLS were stimulated with IL-36α for one week and the effect on proliferation was detected by cell counting and cell labeling with eFluor analysed by flow cytometry. Results: IL-36α signals specific via the MAP-kinase p38 that activates MK2 and HSP27 but no difference in signalling between OA and RA FLS was observed. Activated murine and human FLS showed increased expression of proinflammatory cytokines and MMPs such as IL-6, IL-8, MMP1 and MMP3. This activation was restricted to the binding of IL-36α to its receptor IL-36R due to the lack of activation in IL-36R-/- FLS. MK2-/- FLS showed a decreased activation compared to WT cells after culturing with IL-36α. Additional IL-36α-stimulated FLS showed a significantly increased proliferation compared to unstimulated controls. Conclusions: We show that the activation of FLS through IL-36α is IL-36R and partially MK2 dependent and leads to pathogenic cytokine and MMP production. We conclude that FLS display a target cell for IL-36α in the synovium and this supports the interplay of IL-36α secreting plasma cells with synovial stromal cells.