title: Cigarette smoke inhibits ROCK2 activation in T cells and modulates IL-22 production.
abstract: Gene-environment interactions are known to play a key role in the development of rheumatoid arthritis (RA). Exposure to cigarette smoke (CS) is one of the strongest environmental risk factors associated with RA and has been shown to mediate a range of complex immunomodulatory effects from decreased T and B cell activation to depressed phagocytic function. The effects of CS on the function of TH17 cells, one of the key TH effector subsets implicated in RA pathogenesis, are not fully understood. IRF4 is one of the crucial transcription factors involved in TH-17 differentiation and is absolutely required for the production of IL-17 and IL-21 but, interestingly, inhibits the synthesis of IL-22. The production of IL-17 and IL-21 by IRF4 can be augmented by its phosphorylation by the serine-threonine kinase ROCK2. Given that CS has been reported to increase ROCK activity in endothelial cells, here we investigated the effects of CS on the ROCK2-IRF4 axis in T cells. Surprisingly, we found that CS leads to decreased ROCK2 activation and IRF4 phosphorylation in T cells. This effect was associated with increased IL-22 production. Using a GEF pull-down assay we furthermore identify ARHGEF1 as a key upstream regulator of ROCK2 whose activity in T cells is inhibited by CS. Thus CS can inhibit the ROCK2-IRF4 axis and modulate T cell production of IL-22.
authors.affiliation: Graduate Program in Biochemistry, Cell and Molecular Biology, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA; Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA. Electronic address: chw2019@med.cornell.edu.
authors.forename: Chien-Huan
authors.initials: CH
authors.lastname: Weng
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA. Electronic address: guptasa@hss.edu.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.affiliation: SUNY Downstate Medical Center, 450Clarkson Avenue, Brooklyn, New York, NY 11203, USA. Electronic address: Patrick.Geraghty@downstate.edu.
authors.forename: Patrick
authors.initials: P
authors.lastname: Geraghty
authors.affiliation: SUNY Downstate Medical Center, 450Clarkson Avenue, Brooklyn, New York, NY 11203, USA. Electronic address: robertforonjy@downstate.edu.
authors.forename: Robert
authors.initials: R
authors.lastname: Foronjy
authors.affiliation: Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021, USA; David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021, USA; Department of Medicine, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA. Electronic address: pernisa@hss.edu.
authors.forename: Alessandra B
authors.initials: AB
authors.lastname: Pernis
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D050835:Interferon Regulatory Factors / Q000276:immunology; D007378:Interleukins / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D012907:Smoking / Q000009:adverse effects*; D054460:rho-Associated Kinases / Q000378:metabolism*; D000097043:Interleukin-22; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D007378:Interleukins; D054460:rho-Associated Kinases; D000097043:Interleukin-22; D000099218:Interferon Regulatory Factor-4; C515855:Rock2 protein, mouse