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Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related (GITR)-Fc Fusion Protein Inhibits GITR Triggering and Protects from the Inflammatory Response after Spinal Cord Injury

Dipartimento di Medicina Clinica e Sperimentale, Sezione di Farmacologia, Tossicologia e Chemioterapia, Università di Perugia, Italy (G.N., R.B., C.R.); Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, Messina, Italy (S.C.); and Istituto di Ricovero e Cura a Carattere Scientifico Centro Neurolesi "Bonino-Pulejo," Messina, Italy (T.G., E.M., E.E., D.P.R., P.B.)

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-], 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.

Address correspondence to: Salvatore Cuzzocrea, Dipartimento Clinico e Sperimentale di Medicina e Farmacologia, Torre Biologica, Policlinico Universitario, 98123 Messina, Italy. E-mail: salvator{at}unime.it

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