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.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Nocentini G,Cuzzocrea S,Genovese T,Bianchini R,Mazzon E,Ronchetti S,Esposito E,Rosanna DP,Bramanti P,Riccardi Cdoi
10.1124/mol.107.044354subject
Has Abstractpub_date
2008-06-01 00:00:00pages
1610-21issue
6eissn
0026-895Xissn
1521-0111pii
mol.107.044354journal_volume
73pub_type
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