title: GATA-3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritis.
abstract: OBJECTIVE
  Rheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon-gamma (IFNgamma)-producing Th1 cells or the novel T helper subset, interleukin-17 (IL-17)-producing Th17 cells, are the pathogenic mediators of joint inflammation in chronic nonautoimmune arthritis. Therefore, this study was aimed at examining whether the Th2-specific transcription factor GATA-3 can regulate arthritis, in an experimental murine model, by modulating Th1 and/or Th17 cell polarization.
  
  
  METHODS
  Arthritis was induced with methylated bovine serum albumin (mBSA) in both wild-type and CD2 T cell-specific GATA-3 (CD2-GATA-3)-transgenic mice. At days 1 and 7 after the induction of arthritis, knee joints were scored macroscopically for arthritis severity and for histologic changes. Single-cell suspensions were generated from the spleens, lymph nodes, and inflamed knee joints. Cytokine expression by CD4+ T cells was determined using flow cytometry, and IL-17 expression in the inflamed knee joints was determined by enzyme-linked immunosorbent assay. Analyses of gene expression were performed for Th17-associated factors.
  
  
  RESULTS
  Wild-type mice developed severe joint inflammation, including massive inflammatory cell infiltration and bone erosion that increased significantly over time, reaching maximal arthritis scores at day 7. In contrast, only mild joint inflammation was observed in CD2-GATA-3-transgenic mice. This mild effect was further accompanied by systemic and local reductions in the numbers of IL-17+IFNgamma- and IL-17+IFNgamma+, but not IL-17-IFNgamma+, CD4+ T cells, and by induction of Th2 cytokine expression. Moreover, GATA-3 overexpression resulted in reduced gene expression of the Th17-associated transcription factor retinoic acid-related orphan receptor gammat.
  
  
  CONCLUSIONS
  These results indicate that enforced GATA-3 expression protects against severe joint inflammation and bone erosion in mice, accompanied by reduced differentiation of Th17 cells, but not Th1 cells, during mBSA-induced arthritis.
authors.affiliation: Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands.
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Mus
authors.forename: Marjolein J W
authors.initials: MJ
authors.lastname: de Bruijn
authors.forename: Lisette
authors.initials: L
authors.lastname: de Vogel
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Ferry
authors.initials: F
authors.lastname: Cornelissen
authors.forename: Patrick
authors.initials: P
authors.lastname: Asmawidjaja
authors.forename: Rudi W
authors.initials: RW
authors.lastname: Hendriks
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D001847:Bone Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018801:CD2 Antigens / Q000235:genetics / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D004195:Disease Models, Animal; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D007592:Joint Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D012710:Serum Albumin, Bovine; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism / Q000473:pathology
chemical_list: D018801:CD2 Antigens; D015704:CD4 Antigens; D050990:GATA3 Transcription Factor; C494748:Gata3 protein, mouse; D020381:Interleukin-17; D012710:Serum Albumin, Bovine; D007371:Interferon-gamma