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KMID : 0620920190510070075
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Experimental & Molecular Medicine
2019 Volume.51 No. 7 p.75 ~ p.75
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IRF1 is critical for the TNF-driven interferon response in rheumatoid fibroblast-like synoviocytes
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Bonelli Michael
Dalwigk Karolina
Platzer Alexander
Calvo Isabel Olmos
Hayer Silvia
Niederreiter Birgit
Holinka Johannes
Sevelda Florian
Pap Thomas
Steiner Gunter
Superti-Furga Giulio
Smolen Josef S.
Kiener Hans P.
Karonitsch Thomas
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Abstract
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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.
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KEYWORD
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Chronic inflammation, Interferons
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