PMID- 31285419
OWN - NLM
STAT- MEDLINE
DCOM- 20200622
LR  - 20211204
IS  - 2092-6413 (Electronic)
IS  - 1226-3613 (Print)
IS  - 1226-3613 (Linking)
VI  - 51
IP  - 7
DP  - 2019 Jul 8
TI  - IRF1 is critical for the TNF-driven interferon response in rheumatoid 
      fibroblast-like synoviocytes : JAKinibs suppress the interferon response in 
      RA-FLSs.
PG  - 1-11
LID - 10.1038/s12276-019-0267-6 [doi]
LID - 75
AB  - 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 IFNbeta, 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.
FAU - Bonelli, Michael
AU  - Bonelli M
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Dalwigk, Karolina
AU  - Dalwigk K
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Platzer, Alexander
AU  - Platzer A
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Olmos Calvo, Isabel
AU  - Olmos Calvo I
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Hayer, Silvia
AU  - Hayer S
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Niederreiter, Birgit
AU  - Niederreiter B
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Holinka, Johannes
AU  - Holinka J
AD  - Department of Orthopaedics, Medical University of Vienna, 1090, Vienna, Austria.
FAU - Sevelda, Florian
AU  - Sevelda F
AD  - Department of Orthopaedics, Medical University of Vienna, 1090, Vienna, Austria.
FAU - Pap, Thomas
AU  - Pap T
AD  - Institute of Musculoskeletal Medicine, University Hospital Muenster, 48149, 
      Muenster, Germany.
FAU - Steiner, Gunter
AU  - Steiner G
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
AD  - Ludwig Boltzmann Institute for Arthritis and Rehabilitation, Vienna, Austria.
FAU - Superti-Furga, Giulio
AU  - Superti-Furga G
AD  - CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 
      1090, Vienna, Austria.
FAU - Smolen, Josef S
AU  - Smolen JS
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Kiener, Hans P
AU  - Kiener HP
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria.
FAU - Karonitsch, Thomas
AU  - Karonitsch T
AD  - Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, 
      1090, Vienna, Austria. thomas.karonitsch@meduniwien.ac.at.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190708
PL  - United States
TA  - Exp Mol Med
JT  - Experimental & molecular medicine
JID - 9607880
RN  - 0 (Azetidines)
RN  - 0 (Biomarkers)
RN  - 0 (IRF1 protein, human)
RN  - 0 (Interferon Regulatory Factor-1)
RN  - 0 (Janus Kinase Inhibitors)
RN  - 0 (Piperidines)
RN  - 0 (Purines)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 0 (Pyrroles)
RN  - 0 (Sulfonamides)
RN  - 0 (TNF protein, human)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 87LA6FU830 (tofacitinib)
RN  - 9008-11-1 (Interferons)
RN  - ISP4442I3Y (baricitinib)
SB  - IM
MH  - Animals
MH  - Arthritis, Rheumatoid/*immunology/metabolism/pathology
MH  - Azetidines/therapeutic use
MH  - Biomarkers/metabolism
MH  - Female
MH  - Gene Expression
MH  - Humans
MH  - Inflammation
MH  - Interferon Regulatory Factor-1/genetics/*metabolism
MH  - Interferons/genetics/*metabolism
MH  - Janus Kinase Inhibitors/therapeutic use
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Piperidines/therapeutic use
MH  - Purines
MH  - Pyrazoles
MH  - Pyrimidines/therapeutic use
MH  - Pyrroles/therapeutic use
MH  - Signal Transduction/*drug effects
MH  - Sulfonamides/therapeutic use
MH  - Synovial Membrane/immunology/metabolism/pathology
MH  - Synoviocytes/metabolism
MH  - Tumor Necrosis Factor-alpha/genetics/*metabolism
PMC - PMC6802656
COIS- The authors declare that they have no conflict of interest.
EDAT- 2019/07/10 06:00
MHDA- 2020/06/23 06:00
PMCR- 2019/07/08
CRDT- 2019/07/10 06:00
PHST- 2018/09/03 00:00 [received]
PHST- 2019/03/11 00:00 [accepted]
PHST- 2019/02/20 00:00 [revised]
PHST- 2019/07/10 06:00 [entrez]
PHST- 2019/07/10 06:00 [pubmed]
PHST- 2020/06/23 06:00 [medline]
PHST- 2019/07/08 00:00 [pmc-release]
AID - 10.1038/s12276-019-0267-6 [pii]
AID - 267 [pii]
AID - 10.1038/s12276-019-0267-6 [doi]
PST - epublish
SO  - Exp Mol Med. 2019 Jul 8;51(7):1-11. doi: 10.1038/s12276-019-0267-6.