Common pathways for activation of proinflammatory gene expression by G protein-coupled receptors in primary lung epithelial and endothelial cells.
Acute lung injury is associated with an inflammatory response resulting from the action of multiple mediators. Many proinflammatory mediators released during lung injury exert effects by binding to G protein-coupled receptors (GPCRs). The authors' earlier studies showed that substance P (SP), a ligand for the tachykinin 1 receptor, induced nuclear factor (NF)-kappa B activation and interleukin (IL)-8 up-regulation through a G(q)-dependent pathway. Here the authors extend these findings by examining effects of multiple ligands for G(q)-coupled GPCRs in primary human small airway epithelial cells (SAECs) and rat lung microvessel endothelial cells (RLMVECs). SP, bradykinin, protease activated receptor 2 agonist, and platelet-activating factor (PAF) stimulated IL-8 production in SAECs, whereas only SP and PAF up-regulated CINC-1 (a rat IL-8 homolog) in RLMVECs. Using signaling inhibitors, the authors investigated PAF-induced IL-8 expression and SP-induced CINC-1 expression in primary cells. Signaling cascades were similar in SAECs and RLMVECs and involved phospholipase C/calcium/protein kinase C (PKC) and Ras/Raf/Erk pathways. In addition, the tyrosine kinase inhibitor AG 17 and the proteasome inhibitor MG132 significantly reduced IL-8 and CINC-1 expression induced by GPCR ligands. The results demonstrate a common signaling pathway in primary lung epithelial and endothelial cells, suggesting a generalized mechanism for the induction of proinflammatory gene expression by G(q)-coupled GPCRs following lung injury.
Department of Environmental and Occupational Health Sciences, School of Public Health and Information Sciences, University of Louisville, Louisville, Kentucky 40202, USA.
Weiyuan
W
Chang
Jing
J
Chen
Connie F
CF
Schlueter
Gary W
GW
Hoyle
D000818:Animals; D054360:Chemokine CXCL1 / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000378:metabolism*; D008297:Male; D055806:Microvessels / Q000166:cytology; D010972:Platelet Activating Factor / Q000494:pharmacology; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D015398:Signal Transduction; D013373:Substance P / Q000494:pharmacology
D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D016209:Interleukin-8; D010972:Platelet Activating Factor; D043562:Receptors, G-Protein-Coupled; D013373:Substance P