title: Local activation of STAT-1 and STAT-3 in the inflamed synovium during zymosan-induced arthritis: exacerbation of joint inflammation in STAT-1 gene-knockout mice.
abstract: OBJECTIVE
  STAT proteins play an important role in cytokine signaling. Some investigators have reported preferential activation of STAT-1, and others have reported preferential activation of STAT-3, in response to endogenous interleukin-6 (IL-6), in patients with rheumatoid arthritis. The present study was undertaken to investigate synovial STAT-1 and STAT-3 activation in an experimental animal model of arthritis.
  
  
  METHODS
  Zymosan was injected intraarticularly into naive wild-type (WT), IL-6(-/-), and STAT-1(-/-) mice to induce arthritis. Western blots of synovial lysates were probed with phosphospecific antibodies to detect STAT-1/STAT-3 activation. Inflammation was assessed histologically. Synovial gene expression of the STAT-induced feedback inhibitors suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 in WT and STAT-1(-/-) mice was investigated by reverse transcriptase-polymerase chain reaction.
  
  
  RESULTS
  STAT-3 was activated in inflamed synovium of WT mice throughout the course of disease, whereas activated STAT-1 was observed only during the chronic phase. In IL-6(-/-) mice, STAT activation was limited to STAT-3 on day 1. Although macrophage influx was not inhibited, disease went into remission after day 7 in IL-6(-/-) mice. STAT-1 deficiency resulted in exacerbation of chronic joint inflammation and granuloma formation. In STAT-1(-/-) mice, STAT-3 activation in the inflamed joints was unaltered as compared with WT mice. However, synovial SOCS-1, but not SOCS-3, gene expression was markedly reduced in STAT-1(-/-) mice.
  
  
  CONCLUSIONS
  The results in the IL-6(-/-) mice suggest that STAT-3 is involved in the chronicity of ZIA. Exacerbation of arthritis in STAT-1(-/-) mice suggests an opposing effect of STAT-1, i.e., suppression of joint inflammation. The expression of SOCS-1 could be the underlying mechanism by which STAT-1 controls joint inflammation.
authors.affiliation: University Medical Center Nijmegen, Nijmegen, The Netherlands.
authors.forename: Alfons S K
authors.initials: AS
authors.lastname: de Hooge
authors.forename: Fons A J
authors.initials: FA
authors.lastname: van de Loo
authors.forename: Marije I
authors.initials: MI
authors.lastname: Koenders
authors.forename: Miranda B
authors.initials: MB
authors.lastname: Bennink
authors.forename: Onno J
authors.initials: OJ
authors.lastname: Arntz
authors.forename: Thomas
authors.initials: T
authors.lastname: Kolbe
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
mesh_terms: D000208:Acute Disease; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics; D002908:Chronic Disease; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D015850:Interleukin-6 / Q000235:genetics; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D012097:Repressor Proteins / Q000235:genetics; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D015054:Zymosan
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D015054:Zymosan