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

Salvatore Cuzzocrea, Simona Ronchetti, Tiziana Genovese, Emanuela Mazzon, Massimiliano Agostini, Rosanna Di Paola, Emanuela Esposito, Carmelo Muía, Giuseppe Nocentini, Carlo Riccardi

Research output: Contribution to journalArticle

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, 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-α and interleukin (IL)-1β production; v) nitrotyrosine formation; and vi) NF-κB 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.

Original languageEnglish
Pages (from-to)117-129
Number of pages13
JournalFASEB Journal
Volume21
Issue number1
DOIs
Publication statusPublished - Jan 2007

Keywords

  • Fusion protein
  • Inflammation
  • Mice
  • TNFR superfamily

ASJC Scopus subject areas

  • Agricultural and Biological Sciences (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Cell Biology

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    Cuzzocrea, S., Ronchetti, S., Genovese, T., Mazzon, E., Agostini, M., Di Paola, R., Esposito, E., Muía, C., Nocentini, G., & Riccardi, C. (2007). Genetic and pharmacological inhibition of GITR-GITRL interaction reduces chronic lung injury induced by bleomycin instillation. FASEB Journal, 21(1), 117-129. https://doi.org/10.1096/fj.06-6611com