title: Gene associated with retinoid-interferon-induced mortality 19 attenuates murine autoimmune arthritis by regulation of th17 and treg cells.
abstract: OBJECTIVE
  STAT-3 is a key transcriptional factor in the interleukin-6 (IL-6)-mediated differentiation of Th17 cells. Because Th17 is believed to be a central player in rheumatoid arthritis (RA), we sought to evaluate whether an endogenous inhibitor of the STAT3 gene, GRIM-19 (gene associated with retinoid-interferon-induced mortality 19), could attenuate the progression and severity of murine collagen-induced arthritis (CIA) through suppression of Th17 cells and, reciprocally, could increase expression of Treg cells.
  
  
  METHODS
  Overexpression of GRIM-19 was produced either by intravenous/intramuscular administration of a GRIM-19 overexpression vector in DBA1/J mice or by development of GRIM-19-transgenic (Tg) mice on a C57BL/6 background. Clinical signs were scored for arthritis severity, and mouse splenocytes, serum, and joint tissue were obtained for immunostaining and histologic analyses.
  
  
  RESULTS
  The numbers of CD4+IL-17+ cells and CD4+pSTAT3+ cells were decreased, while the numbers of CD4+CD25+Foxp3+ cells and CD4+pSTAT5+ cells were increased, in both GRIM-19 vector-transfected and GRIM-19-Tg mice. Administration of the GRIM-19 overexpression vector into mice with CIA markedly suppressed the clinical and histologic signs of arthritis in the affected joints. Similarly, when CIA was induced in GRIM-19-Tg mice, the arthritis phenotype was markedly attenuated and the expression of inflammatory cytokines (IL-1β, IL-6, tumor necrosis factor α, and IL-17) in the arthritic joints was also significantly reduced. Moreover, bone marrow-derived monocyte/macrophages obtained from GRIM-19-Tg mice showed attenuated RANKL-induced osteoclastogenesis in vitro.
  
  
  CONCLUSIONS
  GRIM-19 improved the clinical and histologic features of CIA and also inhibited osteoclast formation. These findings suggest that GRIM-19 may be a novel treatment agent for RA.
authors.affiliation: Catholic University of Korea, Seoul, South Korea.
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Moon
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lee
authors.forename: Seon-Yeong
authors.initials: SY
authors.lastname: Lee
authors.forename: Yang-Mi
authors.initials: YM
authors.lastname: Her
authors.forename: Jun-Geol
authors.initials: JG
authors.lastname: Ryu
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Kim
authors.forename: Hea-Jin
authors.initials: HJ
authors.lastname: Son
authors.forename: Seung-Ki
authors.initials: SK
authors.lastname: Kwok
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Chul-Woo
authors.initials: CW
authors.lastname: Yang
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D016207:Cytokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009247:NADH, NADPH Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism* / Q000473:pathology; D058504:Th17 Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D016207:Cytokines; D050796:STAT3 Transcription Factor; D009247:NADH, NADPH Oxidoreductases; C486684:Grim19 protein, mouse