title: Glucocorticoid-induced tumor necrosis factor receptor-related (GITR)-Fc fusion protein inhibits GITR triggering and protects from the inflammatory response after spinal cord injury.
abstract: Glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein is a costimulatory molecule that plays a role in inflammation so that GITR-Fc fusion protein can exert an anti-inflammatory effect. To investigate the mechanism by which GITR-Fc exerts its effects, we first used GITR knock-out (GITR(-/-)) mice to verify whether GITR ligand (GITRL)/GITR system played a pro-inflammatory role in the spinal cord injury (SCI) model. It is noteworthy that less pronounced disease was induced in GITR(-/-) compared with GITR(+/+) mice. We then evaluated the effect of GITR-Fc fusion protein against SCI-induced injuries in GITR(-/-) and wild-type (GITR(+/+)) mice. Administration of GITR-Fc ameliorated SCI-induced inflammation in GITR(+/+) mice as evaluated through: 1) histological damage and apoptosis, 2) modulation of apoptosis-related transduction factors (Bax and Bcl-2), 3) expression of inflammatory markers [nitrotyrosine, inducible nitric-oxide synthase, interleukin (IL)-2, IL-12, and tumor necrosis factor-alpha], and 4) T-lymphocyte infiltration. GITR-Fc was effective in GITR(+/+) but not in GITR(-/-), suggesting that in this experimental model, its anti-inflammatory action was due to inhibition of GITR triggering and not to GITRL activation. In conclusion, GITR plays a role in SCI, and administration of GITR-Fc results in amelioration of SCI severity, prompting further studies on the potential anti-inflammatory properties of GITR-Fc.
authors.affiliation: Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Tossicologia e Chemioterapia, Università di Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Nocentini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Bianchini
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Simona
authors.initials: S
authors.lastname: Ronchetti
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
authors.forename: Di Paola
authors.initials: DP
authors.lastname: Rosanna
authors.forename: Placido
authors.initials: P
authors.lastname: Bramanti
authors.forename: Carlo
authors.initials: C
authors.lastname: Riccardi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism / Q000627:therapeutic use*; D050576:Membrane Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008817:Mice, Mutant Strains; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D013119:Spinal Cord Injuries / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D053450:Glucocorticoid-Induced TNFR-Related Protein; D018836:Inflammation Mediators; D050576:Membrane Fusion Proteins; D018696:Neuroprotective Agents; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse