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.
Skip Nav Destination
Article navigation
May 2008
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
April 25 2008
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;
Donghong He
*The Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, 929 East 57th Street, Chicago, IL 60637, U.S.A.
Search for other works by this author on:
Viswanathan Natarajan;
Viswanathan Natarajan
*The Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, 929 East 57th Street, Chicago, IL 60637, U.S.A.
Search for other works by this author on:
Randi Stern;
Randi Stern
*The Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, 929 East 57th Street, Chicago, IL 60637, U.S.A.
Search for other works by this author on:
Irina A. Gorshkova;
Irina A. Gorshkova
*The Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, 929 East 57th Street, Chicago, IL 60637, U.S.A.
Search for other works by this author on:
Julian Solway;
Julian Solway
*The Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, 929 East 57th Street, Chicago, IL 60637, U.S.A.
Search for other works by this author on:
Ernst Wm. Spannhake;
Ernst Wm. Spannhake
†Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, U.S.A.
Search for other works by this author on:
Yutong Zhao
Yutong Zhao
1
*The Section of Pulmonary and Critical Care, Department of Medicine, Center for Integrative Science Building, 929 East 57th Street, Chicago, IL 60637, U.S.A.
1To whom correspondence should be addressed (email yzhao@medicine.bsd.uchicago.edu).
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
December 07 2007
Revision Received:
January 29 2008
Accepted:
February 25 2008
Accepted Manuscript online:
February 25 2008
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 412 (1): 153–162.
Article history
Received:
December 07 2007
Revision Received:
January 29 2008
Accepted:
February 25 2008
Accepted Manuscript online:
February 25 2008
Citation
Donghong He, Viswanathan Natarajan, Randi Stern, Irina A. Gorshkova, Julian Solway, Ernst Wm. Spannhake, Yutong Zhao; 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. Biochem J 15 May 2008; 412 (1): 153–162. doi: https://doi.org/10.1042/BJ20071649
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.