GATA-3 Protects Against Severe Joint Inflammation and Bone Erosion and Reduces Differentiation of Th17 Cells During Experimental Arthritis

Jan piet Hamburg, Anne-Marie Otten - Mus, Marjolein De Jong - de Bruijn, Lisette Vogel, L Boon, Ferry Cornelissen, Patrick Asmawidjaja, Rudi Hendriks, Erik Lubberts

Research output: Contribution to journalArticleAcademicpeer-review

61 Citations (Scopus)

Abstract

Objective. Rheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon-gamma (IFN gamma)-producing Th1 cells or the novel T helper subset, interieukin-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 in-filtration 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+IFN gamma- and IL-17+IFN gamma+, but not IL-17-IFN gamma+, 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 gamma t. Conclusion. 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.
Original languageUndefined/Unknown
Pages (from-to)750-759
Number of pages10
JournalArthritis & Rheumatism
Volume60
Issue number3
DOIs
Publication statusPublished - 2009

Cite this