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71 LYSOPHOSPHATIDIC ACID INDUCES CYCLOOXYGENASE 2 EXPRESSION AND PROSTAGLANDIN E2 PRODUCTION IN HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS.
  1. Y. Zhao,
  2. D. He,
  3. R. Stern,
  4. S. Kalari,
  5. E. W. Spannhake,
  6. V. Natarajan
  1. The University of Chicago, Chicago, IL; Baltimore, MD.

Abstract

Rationale We have demonstrated that transactivation of EGF-R by lysophosphatidic acid (LPA) partly regulates IL-8 secretion in human bronchial epithelial cells (HBEpCs). The present study provides evidence that crosstalk between G protein-coupled LPA receptors and EGF-R regulates LPA-induced cyclooxygenase 2 (COX-2) expression and prostaglandin E2 (PGE2) production in HBEpCs.

Methods/Results LPA (1 μM) treatment induced COX-2 expression at mRNA and protein levels but had no effect on COX-1 expression. Down-regulation of COX-2 by transfection of COX-2 siRNA blocked LPA-induced PGE2 release in HBEpCs. Pretreatment of HBEpCs with pertussis toxin (PTx), intracellular calcium chelator (BAPTA-AM), overexpression of dominant negative PKC delta, IKK inhibitor (Bay11-7082), JNK inhibitor (JNKi), transfection of c-Jun siRNA, or C/EBPβ siRNA blocked LPA-induced COX-2 expression. Further, down-regulation of EGF-R by EGF-R siRNA or pretreatment with EGF-R tyrosine kinase inhibitor (AG1478) partly attenuated LPA-induced phosphorylation of C/EBPβ, COX-2 expression, and PGE2 release but not phosphorylation of IκB, JNK1/2, and nuclear localization of NF-κB.

Conclusions We show here that LPA induces COX-2 expression through intracellular calcium, activation of PKC delta, NF-κB, JNK/AP-1, C/EBPβ, and EGF-R transactivation. Since COX-2 is anti-inflammatory in the airway, the present results suggest that LPA plays a protective role in airway inflammation and remodeling.

Supported by NIH grant HL 71152 to V.N.

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