Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthritis.
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.
Cuzzocrea
Salvatore
S
Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, Messina, Italy. salvator@unime.it
Ayroldi
Emira
E
Di Paola
Rosanna
R
Agostini
Massimiliano
M
Mazzon
Emanuela
E
Bruscoli
Stefano
S
Genovese
Tiziana
T
Ronchetti
Simona
S
Caputi
Achille P
AP
Riccardi
Carlo
C
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000032:analysis; D051546:Cyclooxygenase 2 / Q000032:analysis; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007371:Interferon-gamma / Q000096:biosynthesis; D019402:Macrophage Inflammatory Proteins / Q000032:analysis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D020556:Neutrophil Infiltration; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000096:biosynthesis
D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D019402:Macrophage Inflammatory Proteins; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C002744:3-nitrotyrosine; D014443:Tyrosine; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2