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Molecular Pharmacology

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Research ArticleArticle

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 and Carlo Riccardi
Molecular Pharmacology June 2008, 73 (6) 1610-1621; DOI: https://doi.org/10.1124/mol.107.044354
Giuseppe Nocentini
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Salvatore Cuzzocrea
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Tiziana Genovese
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Rodolfo Bianchini
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Emanuela Mazzon
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Simona Ronchetti
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Emanuela Esposito
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Di Paola Rosanna
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Placido Bramanti
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Carlo Riccardi
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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-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.

Footnotes

  • This study was supported by Associazione Italiana Ricerca sul Cancro (Milan, Italy) and by the network Fondo per gli Investimenti della Ricerca di Base grant, protocol RBPR05NWWC “CHEM-PROFARMA-NET” (Italy).

  • G.N. and S.C. contributed equally to this work.

  • ABBREVIATIONS: SCI, spinal cord injury; GITR, glucocorticoid-induced tumor necrosis factor receptor-related; GITR-Fc, fusion protein including the extracellular domain of GITR; TNF, tumor necrosis factor; APC, antigen-presenting cell; GITRL, GITR ligand; BBB, Basso, Beattie, and Bresnahan; PBS, phosphate-buffered saline; Ab, antibody; TUNEL, terminal deoxynucleotidyl transferase dUTP nick-end labeling; CFSE, carboxyfluorescein diacetate succinimidyl ester; iNOS, inducible nitric-oxide synthase; wm, white matter; gm, gray matter; IL, interleukin; FasL, Fas ligand; TNF, tumor necrosis factor.

  • ↵ Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

    • Received December 13, 2007.
    • Accepted March 5, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 73 (6)
Molecular Pharmacology
Vol. 73, Issue 6
1 Jun 2008
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Research ArticleArticle

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 and Carlo Riccardi
Molecular Pharmacology June 1, 2008, 73 (6) 1610-1621; DOI: https://doi.org/10.1124/mol.107.044354

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Research ArticleArticle

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 and Carlo Riccardi
Molecular Pharmacology June 1, 2008, 73 (6) 1610-1621; DOI: https://doi.org/10.1124/mol.107.044354
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