$\gamma$-Glutamyltransferase catabolism of S-nitrosoglutathione modulates IL-8 expression in cystic fibrosis bronchial epithelial cells

Title$\gamma$-Glutamyltransferase catabolism of S-nitrosoglutathione modulates IL-8 expression in cystic fibrosis bronchial epithelial cells
Publication TypeJournal Article
Year of Publication2013
AuthorsCorti, A, Bergamini, G, Menegazzi, M, Piaggi, S, Bramanti, E, Scataglini, I, Cianchetti, S, Paggiaro, P, Melotti, P, Pompella, A
JournalFree Radical Biology and Medicine
ISSN08915849 (ISSN)
Keywords$\gamma$-Glutamyltransferase, Article, biocatalysis, bronchus mucosa, cell proliferation, controlled study, Cystic fibrosis, cytokine production, decomposition, down regulation, enzyme activity, epithelium cell, Free radicals, gamma glutamyltransferase, human, human cell, IL-8, immunoglobulin enhancer binding protein, immunomodulation, interleukin 8, intracellular signaling, lipopolysaccharide, messenger RNA, mitogen activated protein kinase 1, mitogen activated protein kinase 3, mitogen activated protein kinase p38, priority journal, protein degradation, protein expression, s nitrosoglutathione, S-nitrosoglutathione

S-nitrosoglutathione (GSNO) is an endogenous nitrosothiol involved in several pathophysiological processes. A role for GSNO has been envisaged in the expression of inflammatory cytokines such as IL-8; however, conflicting results have been reported. $\gamma$-Glutamyltransferase (GGT) enzyme activity can hydrolyze the $\gamma$-glutamyl bond present in the GSNO molecule thus greatly accelerating the release of bioactive nitric oxide. Expression of GGT is induced by oxidative stress, and activated neutrophils contribute to GGT increase in cystic fibrosis (CF) lung exudates by releasing GGT-containing microvesicles. This study was aimed at evaluating the effect of GSNO catabolism mediated by GGT on production of IL-8 in CF transmembrane regulation protein-mutated IB3-1 bronchial cells. The rapid, GGT-catalyzed catabolism of GSNO caused a decrease in both basal and lipopolysaccharide-stimulated IL-8 production in IB3-1 cells, by modulating both NF-$ąppa$B and ERK1/2 pathways, along with a decrease in cell proliferation. In contrast, a slow decomposition of GSNO produced a significant increase in both cell proliferation and expression of IL-8, the latter possibly through p38-mediated stabilization of IL-8 mRNA. Our data suggest that the differential GSNO catabolism mediated by GGT enzyme activity can downregulate the production of IL-8 in CF cells. Hence, the role of GGT activity should be considered when evaluating GSNO for both in vitro and in vivo studies, the more so in the case of GSNO-based therapies for cystic fibrosis. © 2013 Elsevier Inc.