Glucocorticoid-induced tumor necrosis factor receptor family-related protein exacerbates collagen-induced arthritis by enhancing the expansion of Th17 cells

Am J Pathol. 2012 Mar;180(3):1059-1067. doi: 10.1016/j.ajpath.2011.11.018. Epub 2011 Dec 31.


Rheumatoid arthritis (RA), a chronic autoimmune form of inflammatory joint disease, progressively affects multiple joints with pathological changes in the synovia, cartilage, and bone. Numerous studies have suggested a critical role for glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) in the pathogenesis of autoimmune arthritis by modulating both innate and adaptive immune reactions, but the underlying mechanisms by which GITR activation promotes arthritic progression remain largely unclear. In this study, we found that collagen-induced arthritis mice treated with the ligand of GITR (GITRL) displayed an earlier onset of arthritis with a markedly increased severity of arthritic symptoms and joint damage, in which significantly increased Th17 cells in both spleen and draining lymph nodes were observed. Notably, results showed that a marked expansion of Th17 cells with increased RORγt mRNA expression was induced from naïve CD4(+) T cells when cultured with GITRL. Consistently, normal mice that were treated with GITRL were found to display a substantial expansion of splenic Th17 cells. Furthermore, we detected elevated serum levels of GITRL in patients with RA, which were positively correlated with an increase in interleukin-17 production. Taken together, the results from this study have revealed a new function of GITRL in exacerbating autoimmune arthritis via the enhancement of the expansion of Th17 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Experimental / etiology*
  • Arthritis, Experimental / pathology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Differentiation
  • Cell Division / physiology
  • Glucocorticoid-Induced TNFR-Related Protein / metabolism
  • Glucocorticoid-Induced TNFR-Related Protein / pharmacology
  • Glucocorticoid-Induced TNFR-Related Protein / physiology*
  • Humans
  • Interleukin-17 / metabolism
  • Ligands
  • Lymph Nodes / pathology
  • Male
  • Mice
  • Mice, Inbred DBA
  • Recombinant Proteins
  • Spleen / pathology
  • Th17 Cells / metabolism
  • Th17 Cells / pathology*


  • Glucocorticoid-Induced TNFR-Related Protein
  • Interleukin-17
  • Ligands
  • Recombinant Proteins