Endothelin-1 induces proliferation of human lung fibroblasts and IL-11 secretion through an ETA receptor-dependent activation of map kinases

✍ Scribed by Luca Gallelli; Girolamo Pelaia; Bruno D'Agostino; Giovanni Cuda; Alessandro Vatrella; Donatella Fratto; Vincenza Gioffrè; Umberto Galderisi; Marilisa De Nardo; Claudio Mastruzzo; Elisa Trovato Salinaro; Mauro Maniscalco; Matteo Sofia; Nunzio Crimi; Francesco Rossi; Mario Caputi; Francesco S. Costanzo; Rosario Maselli; Serafino A. Marsico; Carlo Vancheri

• Book ID: 102301990
• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 232 KB
• Volume: 96
• Category: Article
• ISSN: 0730-2312
• DOI: 10.1002/jcb.20608

✦ Synopsis

Abstract

Endothelin‐1 (ET‐1) is implicated in the fibrotic responses characterizing interstitial lung diseases, as well as in the airway remodeling process occurring in asthma. Within such a context, the aim of our study was to investigate, in primary cultures of normal human lung fibroblasts (NHLFs), the ET‐1 receptor subtypes, and the intracellular signal transduction pathways involved in the proliferative effects of this peptide. Therefore, cells were exposed to ET‐1 in the presence or absence of an overnight pre‐treatment with either ET~A~ or ET~B~ selective receptor antagonists. After cell lysis, immunoblotting was performed using monoclonal antibodies against the phosphorylated, active forms of mitogen‐activated protein kinases (MAPK). ET‐1 induced a significant increase in MAPK phosphorylation pattern, and also stimulated fibroblast proliferation and IL‐6/IL‐11 release into cell culture supernatants. All these effects were inhibited by the selective ET~A~ antagonist BQ‐123, but not by the specific ET~B~ antagonist BQ‐788. The stimulatory influence of ET‐1 on IL‐11, but not on IL‐6 secretion, was prevented by MAPK inhibitors. Therefore, such results suggest that in human lung fibroblasts ET‐1 exerts a profibrogenic action via an ET~A~ receptor‐dependent, MAPK‐mediated induction of IL‐11 release and cell proliferation. © 2005 Wiley‐Liss, Inc.