Glucocorticoid-induced tumor necrosis factor receptor-related (GITR)-Fc fusion protein inhibits GITR triggering and protects from the inflammatory response after spinal cord injury

Giuseppe Nocentini, Salvatore Cuzzocrea, Tiziana Genovese, Rodolfo Bianchini, Emanuela Mazzon, Simona Ronchetti, Emanuela Esposito, Di Paola Rosanna, Placido Bramanti, Carlo Riccardi

Research output: Contribution to journalArticle

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 antiinflammatory 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.

Original languageEnglish
Pages (from-to)1610-1621
Number of pages12
JournalMolecular Pharmacology
Volume73
Issue number6
DOIs
Publication statusPublished - Jun 2008

ASJC Scopus subject areas

  • Pharmacology

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