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IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes
Michael Bonelli,Karolina Dalwigk,Alexander Platzer,Isabel Olmos Calvo,Silvia Hayer,Birgit Niederreiter,Johannes Holinka,Florian Sevelda,Thomas Pap,Günter Steiner,Giulio Superti-Furga,Josef S. Smolen,H 생화학분자생물학회 2019 Experimental and molecular medicine Vol.51 No.-
Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovial inflammation. The major drivers of synovial inflammation are cytokines and chemokines. Among these molecules, TNF activates fibroblast-like synoviocytes (FLSs), which leads to the production of inflammatory mediators. Here, we show that TNF regulates the expression of the transcription factor interferon regulatory factor 1 (IRF1) in human FLSs as well as in a TNF transgenic arthritis mouse model. Transcriptomic analyses of IRF1-deficient, TNF-stimulated FLSs define the interferon (IFN) pathway as a major target of IRF1. IRF1 expression is associated with the expression of IFNβ, which leads to the activation of the JAK-STAT pathway. Blocking the JAK-STAT pathway with the Janus kinase inhibitor (JAKinib) baricitinib or tofacitinib reduces the expression of IFN-regulated genes (IRGs) in TNF-activated FLSs. Therefore, we conclude that TNF induces a distinct inflammatory cascade, in which IRGs are key elements, in FLSs. The IFN-signature might be a promising biomarker for the efficient and personalized use of new treatment strategies for RA, such as JAKinibs.