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Lysophosphatidic Acid-induced Transactivation Of Epidermal Growth Factor Receptor Regulates Cyclo-oxygenase-2 Expression And Prostaglandin E2 Release Via C/EBPβ In Human Bronchial Epithelial Cells

Donghong He, Viswanathan Natarajan, Randi Stern, Irina A. Gorshkova, Julian Solway, Ernst Wm. Spannhake, Yutong Zhao

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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 PGE2 [PG (prostaglandin) E2] release through the transcriptional factor, C/EBPβ (CCAAT/enhancer-binding protein β), in HBEpCs. Treatment with LPA (1 μM) stimulated COX-2 mRNA and protein expression and PGE2 release via Gαi-coupled LPARs (LPA receptors). Pretreatment with inhibitors of NF-κB (nuclear factor-κB), JNK (Jun N-terminal kinase), or down-regulation of c-Jun or C/EBPβ 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/EBPβ; however, neither of these factors had an effect on the NF-κB and JNK pathways. Furthermore, LPA-induced EGFR transactivation, phosphorylation of C/EBPβ 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 PKCζ [PKC (protein kinase C) ζ] peptide pseudosubstrate. Overexpression of the PLD2-K758R mutant also attenuated LPA-induced phosphorylation and activation of PKCζ. These results demonstrate that LPA induces COX-2 expression and PGE2 production through EGFR transactivation-independent activation of transcriptional factors NF-κB and c-Jun, and EGFR transactivation-dependent activation of C/EBPβ in HBEpCs. Since COX-2 and PGE2 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.