title: Lysophosphatidic acid-induced transactivation of epidermal growth factor receptor regulates cyclo-oxygenase-2 expression and prostaglandin E(2) release via C/EBPbeta in human bronchial epithelial cells.
abstract: We have demonstrated that LPA (lysophosphatidic acid)-induced IL (interleukin)-8 secretion was partly mediated via transactivation of EGFR [EGF (epidermal growth factor) receptor] in HBEpCs (human bronchial epithelial primary cells). The present study provides evidence that LPA-induced transactivation of EGFR regulates COX (cyclo-oxygenase)-2 expression and PGE(2) [PG (prostaglandin) E(2)] release through the transcriptional factor, C/EBPbeta (CCAAT/enhancer-binding protein beta), in HBEpCs. Treatment with LPA (1 microM) stimulated COX-2 mRNA and protein expression and PGE(2) release via G(alphai)-coupled LPARs (LPA receptors). Pretreatment with inhibitors of NF-kappaB (nuclear factor-kappaB), JNK (Jun N-terminal kinase), or down-regulation of c-Jun or C/EBPbeta with specific siRNA (small interference RNA) attenuated LPA-induced COX-2 expression. Downregulation of EGFR by siRNA or pretreatment with the EGFR tyrosine kinase inhibitor, AG1478, partly attenuated LPA-induced COX-2 expression and phosphorylation of C/EBPbeta; however, neither of these factors had an effect on the NF-kappaB and JNK pathways. Furthermore, LPA-induced EGFR transactivation, phosphorylation of C/EBPbeta and COX-2 expression were attenuated by overexpression of a catalytically inactive mutant of PLD2 [PLD (phospholipase D) 2], PLD2-K758R, or by addition of myristoylated PKCzeta [PKC (protein kinase C) zeta] peptide pseudosubstrate. Overexpression of the PLD2-K758R mutant also attenuated LPA-induced phosphorylation and activation of PKCzeta. These results demonstrate that LPA induces COX-2 expression and PGE(2) production through EGFR transactivation-independent activation of transcriptional factors NF-kappaB and c-Jun, and EGFR transactivation-dependent activation of C/EBPbeta in HBEpCs. Since COX-2 and PGE(2) have been shown to be anti-inflammatory in airway inflammation, the present data suggest a modulating and protective role of LPA in regulating innate immunity and remodelling of the airways.
authors.affiliation: The Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, 929 East 57th Street, Chicago, IL 60637, USA.
authors.forename: Donghong
authors.initials: D
authors.lastname: He
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Randi
authors.initials: R
authors.lastname: Stern
authors.forename: Irina A
authors.initials: IA
authors.lastname: Gorshkova
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.forename: Ernst Wm
authors.initials: EW
authors.lastname: Spannhake
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015232:Dinoprostone / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D010739:Phospholipase D / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D008246:Lysophospholipids; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D051546:Cyclooxygenase 2; C081975:protein kinase C eta; D066246:ErbB Receptors; D011493:Protein Kinase C; D010739:Phospholipase D; D015232:Dinoprostone; C032881:lysophosphatidic acid