P054 IRF-1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes. (March 2019)

• Record Type: Journal Article
• Authors: Bonelli, M; Dalwigk, K; Platzer, A; Calvo, I; Hayer, S; Niederreiter, B; Holinka, J; Sevelda, F; Pap, T; Steiner, G; Superti-Furga, G; Smolen, J; Kiener, H; Karonitsch, T
• Is Part Of: Annals of the rheumatic diseases. Volume 78(2019)Supplement 1
• Page Start: A23
• Page End: A23
• Publication Date: 2019-03
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2018-EWRR2019.46
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Career situation of first and presenting author: Young investigator. Introduction: Rheumatoid arthritis (RA) is an autoimmune disease, which is characterized by persistent, synovial inflammation. Major drivers of synovial inflammation are cytokines and chemokines. Among them TNF activates fibroblast-like synoviocytes (FLS), which leads to the production of inflammatory mediators. The pathways and transcription factors that determine the inflammatory response in FLS are largely unexplored. Here, we investigated the potential contribution of the transcription-factor IRF1 to the inflammatory gene expression in FLS. Methods: Expression of IRF1 in synovial tissues was assessed by immunohistochemistry (IHC). RA-FLS were isolated according to established protocols and cultured using 2-D or 3-D culture techniques. IRF1 expression in response to TNF was determined by western blots, qPCR or IHC. FLS were also stimulated with TNF in the presence or absence of IRF1 siRNA pools. Global changes of mRNA expression were assessed by RNA-sequencing. Janus kinase activity was blocked by baricitinib or tofacitinib. Results: Our data reveal that TNF regulates the expression of IRF1 in human FLS as well as in the huTNFtg mouse model of arthritis. Transcriptomic analyses of IRF-1-deficient TNF-stimulated FLS define the interferon (IFN) pathway as a major target of IRF-1. Further experiments show that TNF-induced IRF-1 expression promotes the expression of IFN-β, which leads to an activation of the JAK-STAT pathway. Blockade of the JAK-STAT pathway, by the Janus kinase inhibitors baricitinib or tofacitinib, reduces the expression of IFN-regulated genes (IRGs), such as CXCL9, CXCL10, CXCL11 and TNFSF13B, in TNF-activated FLS. Conclusions: Our data reveal that IRF1 is crucial for the IFN-response of FLS and support the idea that IRF1 plays a critical role for the development of synovial inflammation. Disclosure of Interest: None declared.