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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.
Syndecan-4 regulates ADAMTS-5 activation and cartilage breakdown in osteoarthritis
Echtermeyer, Frank,Bertrand, Jessica,Dreier, Rita,Meinecke, Ingmar,Neugebauer, Katja,Fuerst, Martin,Lee, Yun Jong,Song, Yeong Wook,Herzog, Christine,Theilmeier, Gregor,Pap, Thomas Nature Publishing Group 2009 Nature medicine Vol.15 No.9
Aggrecan cleavage by a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 5 (ADAMTS-5) is crucial for the breakdown of cartilage matrix during osteoarthritis, a degenerative joint disease that leads to the progressive destruction of articular structures. The mechanisms of ADAMTS-5 activation and their links to the pathogenesis of osteoarthritis remain poorly understood, but syndecans have been shown to be involved in the activation of ADAMTS-4 (ref. 3). Here we show that syndecan-4 is specifically induced in type X collagen–producing chondrocytes both in human osteoarthritis and in murine models of the disease. The loss of syndecan-4 in genetically modified mice and intra-articular injections of syndecan-4–specific antibodies into wild-type mice protect from proteoglycan loss and thereby prevent osteoarthritic cartilage damage in a surgically induced model of osteoarthritis. The occurrence of less severe osteoarthritis-like cartilage destruction in both syndecan-4–deficient mice and syndecan-4–specific antibody–treated wild-type mice results from a marked decrease in ADAMTS-5 activity. Syndecan-4 controls the activation of ADAMTS-5 through direct interaction with the protease and through regulating mitogen-activated protein kinase (MAPK)-dependent synthesis of matrix metalloproteinase-3 (MMP-3). Our data suggest that strategies aimed at the inhibition of syndecan-4 will be of great value for the treatment of cartilage damage in osteoarthritis.
Apolipoprotein B binds to enolase-1 and aggravates inflammation in rheumatoid arthritis
Lee, Joo Youn,Kang, Min Jueng,Choi, Ji Yong,Park, Ji Soo,Park, Jin Kyun,Lee, Eun Young,Lee, Eun Bong,Pap, Thomas,Yi, Eugene C,Song, Yeong Wook H. K. Lewis 2018 Annals of the rheumatic diseases Vol. No.
<P>Conclusions A key component of atherogenic lipids, apoB, aggravated arthritis by potentiating the inflammatory response via its interaction with ENO1 expressed on the surface of immune cells. This suggests a novel mechanism by which lipid metabolism regulates chronic inflammation in RA.</P>