title: SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts.
abstract: Cigarette smoking is a recognized environmental risk factor for the development and progression of rheumatoid arthritis (RA). RA synovial fibroblasts (RASF) actively contribute to inflammation and joint destruction in this chronic inflammatory autoimmune disease. In the current study, we investigated the influence of cigarette smoke on the inflammatory and matrix-destructive properties of RASF. Furthermore, the functional role of Sirtuin 6 (SIRT6) in the regulation of the signalling induced by cigarette smoke or by tumor necrosis factor alpha (TNFα) was elucidated. We demonstrated that stimulation with cigarette smoke extract (CSE) enhances the pro-inflammatory and matrix-destructive potential of RASF by inducing the production of pro-inflammatory cytokine interleukin 8 (IL8) and the matrix-destructive enzyme matrix metalloproteinase 1 (MMP1), but not of IL6 and MMP3. Moreover, we could show that the expression of MMP1 is specifically regulated by SIRT6. Treatment of RASF with CSE or TNFα increased the levels of SIRT6. The expression of SIRT6 was also enhanced in vivo in synovial tissues of RA smokers and in joints of mice exposed to cigarette smoke. Silencing of SIRT6 specifically increased basal as well as CSE- and TNFα-induced production of MMP1, demonstrating that SIRT6 plays an important role in restricting MMP1 expression. In conclusion, the upregulation of SIRT6 in RASF under CSE or TNFα stimulation functions as a counterregulatory mechanism attenuating the production of the matrix-destructive enzyme MMP1. This is the first study revealing the protective function of SIRT6 in the cigarette smoke-induced signalling.
  
  
  CONCLUSIONS
  Cigarette smoke induces pro-inflammatory and matrix-destructive responses in RASF. Cigarette smoke enhances the expression of SIRT6 in vitro and in vivo. TNFα increases the levels of SIRT6. SIRT6 diminishes MMP1 production under cigarette smoke extract and TNFα stimulation.
authors.affiliation: Center of Experimental Rheumatology, University Hospital Zurich, Gloriastrasse 25, 8091, Zurich, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Engler
authors.forename: Fabienne
authors.initials: F
authors.lastname: Niederer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klein
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.forename: Diego
authors.initials: D
authors.lastname: Kyburz
authors.forename: Giovanni G
authors.initials: GG
authors.lastname: Camici
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Caroline
authors.initials: C
authors.lastname: Ospelt
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D002478:Cells, Cultured; D045424:Complex Mixtures / Q000009:adverse effects*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D012906:Smoke / Q000009:adverse effects*; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism; D014026:Nicotiana; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C508606:CXCL8 protein, human; D045424:Complex Mixtures; D016209:Interleukin-8; D012333:RNA, Messenger; D012906:Smoke; D014409:Tumor Necrosis Factor-alpha; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1; D037761:Sirtuins