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

Abstract

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, dendritic 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-alpha and interleukin (IL)-1beta production; v) nitrotyrosine formation; and vi) NF-kappaB activation. The cotreatment of GITR+/+ mice with Fc-GITR fusion protein (6.25 microg/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.

• Authors: Salvatore Cuzzocrea, Simona Ronchetti, Tiziana Genovese, Emanuela Mazzon, Massimiliano Agostini, Rosanna Di Paola, Emanuela Esposito, Carmelo Muià, Giuseppe Nocentini, Carlo Riccardi
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 21 Issue 1 Pg. 117-29 (Jan 2007) ISSN: 1530-6860 [Electronic] United States
• PMID: 17135359 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Glucocorticoid-Induced TNFR-Related Protein
• Interleukin-1
• Receptors, Nerve Growth Factor
• Receptors, Tumor Necrosis Factor
• Tnfrsf18 protein, mouse
• Tnfsf18 protein, mouse
• Tumor Necrosis Factor-alpha
• Tumor Necrosis Factors
• Bleomycin
• Peroxidase

Topics

• Animals
• Bleomycin (pharmacology)
• Female
• Glucocorticoid-Induced TNFR-Related Protein
• Interleukin-1 (biosynthesis)
• Lung (drug effects, enzymology, metabolism)
• Male
• Mice
• Peroxidase (metabolism)
• Protein Binding
• Receptors, Nerve Growth Factor (metabolism)
• Receptors, Tumor Necrosis Factor (metabolism)
• Tumor Necrosis Factor-alpha (biosynthesis)
• Tumor Necrosis Factors (metabolism)