Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis.

Abstract

In rheumatoid arthritis (RA), a widespread autoimmune/inflammatory joint disease, early activation of effector CD4+ T lymphocytes, and cytokine production is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, and disease. GITR (glucocorticoid-induced TNFR family-related gene), a costimulatory molecule for T lymphocytes, increases CD4+CD25- effector T cell activation while inhibiting suppressor activity of CD4+CD25+ T regulatory (Treg) cells. We analyzed the role of GITR in type II collagen (CII) -induced arthritis (CIA) using GITR-/- and GITR+/+ mice. Results indicate significantly less CIA induction in GITR-/- mice than in GITR+/+ mice, with marked differences in erythema, edema, neutrophil infiltration, joint injury, and bone erosion. Production of IFNgamma, IL-6, TNFalpha, MIP-1alpha, and MIP-2, inducible NOS (iNOS), COX-2, and nitrotyrosine poly-ADP-ribose (PAR) were also less in CII-treated GITR-/- mice. Although CD4+CD25+ Treg cells from GITR+/+ and GITR-/- CII-challenged mice exerted similar suppressor activity in vitro, GITR triggering abrogated GITR+/+ Treg suppressor activity and costimulated CD4+CD25- GITR+/+ effector cells. Furthermore, Treg cells from GITR-/- protected more than Treg cells from GITR+/+ mice against CIA when cotransferred with Treg-depleted splenocytes from arthritic GITR+/+ animals into severe combined immunodeficient (SCID) mice. In conclusion, GITR plays a critical role in the immunological response against CII and in the development of CIA.

• Authors: Salvatore Cuzzocrea, Emira Ayroldi, Rosanna Di Paola, Massimiliano Agostini, Emanuela Mazzon, Stefano Bruscoli, Tiziana Genovese, Simona Ronchetti, Achille P Caputi, Carlo Riccardi
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 19 Issue 10 Pg. 1253-65 (Aug 2005) ISSN: 1530-6860 [Electronic] United States
• PMID: 16051692 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL3
• Chemokine CCL4
• Chemokine CXCL2
• Chemokines
• Cxcl2 protein, mouse
• Glucocorticoid-Induced TNFR-Related Protein
• Macrophage Inflammatory Proteins
• Receptors, Nerve Growth Factor
• Receptors, Tumor Necrosis Factor
• Tnfrsf18 protein, mouse
• Tumor Necrosis Factor-alpha
• 3-nitrotyrosine
• Tyrosine
• Interferon-gamma
• Nitric Oxide Synthase Type II
• Cyclooxygenase 2

Topics

• Animals
• Arthritis, Experimental (etiology, immunology, pathology)
• Chemokine CCL3
• Chemokine CCL4
• Chemokine CXCL2
• Chemokines (analysis)
• Cyclooxygenase 2 (analysis)
• Female
• Glucocorticoid-Induced TNFR-Related Protein
• Interferon-gamma (biosynthesis)
• Macrophage Inflammatory Proteins (analysis)
• Male
• Mice
• Mice, SCID
• Neutrophil Infiltration
• Nitric Oxide Synthase Type II (analysis)
• Receptors, Nerve Growth Factor (genetics)
• Receptors, Tumor Necrosis Factor (genetics)
• T-Lymphocytes, Regulatory (physiology)
• Tumor Necrosis Factor-alpha (biosynthesis)
• Tyrosine (analogs & derivatives, biosynthesis)