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

• Published in: The FASEB journal 2005-08, Vol.19 (10), p.1253-1265
• Main Authors: Cuzzocrea, Salvatore, Ayroldi, Emira, Di Paola, Rosanna, Agostini, Massimiliano, Mazzon, Emanuela, Bruscoli, Stefano, Genovese, Tiziana, Ronchetti, Simona, Caputi, Achille P, Riccardi, Carlo
• Format: Article
• Language: English
• Subjects: Animals; Arthritis, Experimental - etiology; Arthritis, Experimental - immunology; Arthritis, Experimental - pathology; Chemokine CCL3; Chemokine CCL4; Chemokine CXCL2; chemokines; 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; rheumatoid arthritis; T lymphocyte activity; T-Lymphocytes, Regulatory - physiology; Tumor Necrosis Factor-alpha - biosynthesis; Tyrosine - analogs & derivatives; Tyrosine - biosynthesis
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.04-3556com

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 IFN[gamma], IL-6, TNF[alpha], MIP-1[alpha], 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.--Cuzzocrea, S., Ayroldi, E., Di Paola, R., Agostini, M., Mazzon, E., Bruscoli, S., Genovese, T., Ronchetti, S., Caputi, A. P., Riccardi, C. Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis.