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Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation

Salvatore Cuzzocrea^*,1,2, Simona Ronchetti^,1, Tiziana Genovese^*,, Emanuela Mazzon^*,, Massimiliano Agostini, Rosanna Di Paola^*, Emanuela Esposito, Carmelo Muià^*, Giuseppe Nocentini and Carlo Riccardi

^* Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Messina, Italy;

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Centro Neurolesi "Bonino-Pulejo," Messina, Italy;

Department of Clinical and Experimental Medicine and Pharmacology, Section of Pharmacology, Tossicology and Chemioterapy, University of Perugia, and Polo Scientifico e Didattico di Terni, Terni, Italy; and

Department of Experimental Pharmacology, University of Naples "Federico II," Naples, Italy

²Correspondence: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Torre Biologica, Policlinico Universitario Via C. Valeria, Gazzi, 98100 Messina Italy. E-mail: salvator{at}unime.it

We have recently identified a gene named GITR (glucocorticoid-induced TNF receptor related gene). GITR is expressed in different cells and tissues such as T lymphocytes from thymus and spleen and lymph nodes, and also in the lung. GITR ligand (GITRL) is expressed in several cells including macrophages, B cells, denditric cells, and endothelial cells. In the present study, by comparing the responses in wild-type (WT) mice (GITR^+/+) and GITR-deficient mice (GITR^–/–), we investigated the role played by GITR-GITRL interaction in the development of chronic lung injury caused by bleomycin instillation. When compared with bleomycin-treated GITR^+/+ mice, bleomycin-treated GITR^–/– mice exhibited a reduced degree of i) lung infiltration with polymorphonuclear neutrophils (MPO activity); ii) edema formation; iii) histological evidence of lung injury; iv) TNF- and interleukin (IL)-1ß production; v) nitrotyrosine formation; and vi) NF-B activation. The cotreatment of GITR^+/+ mice with Fc-GITR fusion protein (6.25 µg/mouse) also significantly attenuated all of the above indicators of lung damage and inflammation. Our results clearly demonstrate that GITR-GITRL interaction plays an important role in the chronic lung injury induced by bleomycin in the mice.—Cuzzocrea, S., Ronchetti, S., Genovese, T., Mazzon, E., Agostini, M., Di Paola, R., Esposito, E., Muià, C., Nocentini, G., Riccardi, C. Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation.

Key Words: TNFR superfamily • mice • inflammation • fusion protein

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				S. Ronchetti, G. Nocentini, R. Bianchini, L. T. Krausz, G. Migliorati, and C. Riccardi Glucocorticoid-Induced TNFR-Related Protein Lowers the Threshold of CD28 Costimulation in CD8+ T Cells J. Immunol., November 1, 2007; 179(9): 5916 - 5926. [Abstract] [Full Text] [PDF]

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