Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation.
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.
Cuzzocrea
Salvatore
S
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. salvator@unime.it
Ronchetti
Simona
S
Genovese
Tiziana
T
Mazzon
Emanuela
E
Agostini
Massimiliano
M
Di Paola
Rosanna
R
Esposito
Emanuela
E
Muià
Carmelo
C
Nocentini
Giuseppe
G
Riccardi
Carlo
C
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology*; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007375:Interleukin-1 / Q000096:biosynthesis; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D009195:Peroxidase / Q000378:metabolism; D011485:Protein Binding; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048069:Tumor Necrosis Factors / Q000378:metabolism*
D053450:Glucocorticoid-Induced TNFR-Related Protein; D007375:Interleukin-1; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; D001761:Bleomycin; D009195:Peroxidase