Online citations, reference lists, and bibliographies.
← Back to Search

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

Save to my Library
Download PDF
Analyze on Scholarcy
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.