Role of acylglycerol kinase in LPA-induced IL-8 secretion and transactivation of epidermal growth factor-receptor in human bronchial epithelial cells

• Published in: American journal of physiology. Lung cellular and molecular physiology 2009-03, Vol.296 (3), p.L328-L336
• Main Authors: Kalari, Satish, Zhao, Yutong, Spannhake, Ernst Wm, Berdyshev, Evgeny V, Natarajan, Viswanathan
• Format: Article
• Language: English
• Subjects: Base Sequence; Biochemistry; Bronchi - cytology; Bronchi - drug effects; Bronchi - physiology; Cells; Cells, Cultured; DNA Primers - genetics; Epithelial Cells - drug effects; Epithelial Cells - physiology; ErbB Receptors - genetics; Humans; Interleukin-8 - metabolism; Kinases; Lipids; Lungs; Lysophospholipids - metabolism; Lysophospholipids - pharmacology; MAP Kinase Signaling System - drug effects; NF-kappa B - metabolism; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Proteins; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; Subcellular Fractions - enzymology; Transcriptional Activation - drug effects; Transfection
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.90431.2008

1 Department of Medicine, Section of Pulmonary and Critical Care Medicine, 2 The University of Chicago, Chicago, Illinois Submitted 6 August 2008 ; accepted in final form 15 December 2008 LPA (lysophosphatidic acid) is a potent bioactive phospholipid, which regulates a number of diverse cellular responses through G protein-coupled LPA receptors. Intracellular LPA is generated by the phosphorylation of monoacylglycerol by acylglycerol kinase (AGK); however, the role of intracellular LPA in signaling and cellular responses remains to be elucidated. Here, we investigated signaling pathways of IL-8 secretion mediated by AGK and intracellular LPA in human bronchial epithelial cells (HBEpCs). Expression of AGK in HBEpCs was detected by real-time PCR, and overexpressed AGK was mainly localized in mitochondria as determined by immunofluorescence and confocal microscopy. Overexpression of lentiviral AGK wild type increased intracellular LPA production ( 1.8-fold), enhanced LPA-mediated IL-8 secretion, and stimulated tyrosine phosphorylation epidermal growth factor-receptor (EGF-R). Furthermore, downregulation of native AGK by AGK small interfering RNA decreased intracellular LPA levels ( 2-fold) and attenuated LPA-induced p38 MAPK, JNK, and NF- B activation, tyrosine phosphorylation of EGF-R, and IL-8 secretion. These results suggest that native AGK regulates LPA-mediated IL-8 secretion involving MAPKs, NF- B, and transactivation of EGF-R. Thus AGK may play an important role in innate immunity and airway remodeling during inflammation. lysophosphatidic acid; signal transduction; MAPKs; NF- B Address for reprint requests and other correspondence: V. Natarajan, Dept. of Medicine, CIS Bldg., Suite #W408B, 929 East 57th St., Chicago, IL 60637 (e-mail: vnataraj{at}medicine.bsd.uchicago.edu )