Received for publication December 13, 2007.
Revised March 4, 2008.
Accepted for publication March 5, 2008.

GITR-FC FUSION PROTEIN INHIBITS GITR TRIGGERING AND PROTECTS FROM THE INFLAMMATORY RESPONSE FOLLOWING SPINAL CORD INJURY

Abstract

Glucocorticoid-Induced Tumor necrosis factor receptor-Related (GITR) protein is a co-stimulatory 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 GITRL/GITR system played a pro-inflammatory role in the spinal cord injury (SCI) model. Notably, a less pronounced disease was induced in GITR^-/- as compared to 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, iNOS, IL-2, IL-12 and TNF-) 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 is 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.

Key words: Tumor necrosis factor, Glucorticoids/Mineralocorticoids, NFkappaB, Knockout