%0 Journal Article %A Giuseppe Nocentini %A Salvatore Cuzzocrea %A Tiziana Genovese %A Rodolfo Bianchini %A Emanuela Mazzon %A Simona Ronchetti %A Emanuela Esposito %A Di Paola Rosanna %A Placido Bramanti %A Carlo Riccardi %T Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related (GITR)-Fc Fusion Protein Inhibits GITR Triggering and Protects from the Inflammatory Response after Spinal Cord Injury %D 2008 %R 10.1124/mol.107.044354 %J Molecular Pharmacology %P 1610-1621 %V 73 %N 6 %X 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-α], 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. The American Society for Pharmacology and Experimental Therapeutics %U https://molpharm.aspetjournals.org/content/molpharm/73/6/1610.full.pdf