Lysophosphatidic acid induces interleukin-13 (IL-13) receptor α2 expression and inhibits IL-13 signaling in primary human bronchial epithelial cells

Yutong Zhao, Donghong He, Jing Zhao, Lixin Wang, Alan R. Leff, Ernst Wm Spannhake, Steve Georas, Viswanathan Natarajan

Research output: Contribution to journalArticlepeer-review

Abstract

Interleukin-13 (IL-13), a Th2 cytokine, plays a pivotal role in pathogenesis of bronchial asthma via IL-13 receptor α1 (IL-13Rα1) and IL-4 receptor α(IL-4Rα). Recent studies show that a decoy receptor for IL-13, namely IL-13Rα2, mitigates IL-13 signaling and function. This study provides evidence for regulation of IL-13Rα2 production and release and IL-13-dependent signaling by lysophosphatidic acid (LPA) in primary cultures of human bronchial epithelial cells (HBEpCs). LPA treatment of HBEpCs in a time-dependent fashion increased IL-13Rα2 gene expression without altering the mRNA levels of IL-13Rα1 and IL-4Rα. Pretreatment with pertussis toxin (100 ng/ml, 4 h) or transfection of c-Jun small interference RNA or an inhibitor of JNK attenuated LPA-induced IL-13Rα2 gene expression and secretion of soluble IL-13Rα2. Overexpression of catalytically inactive mutants of phospholipase D(PLD) 1 or 2 attenuated LPA-induced IL-13Rα2 gene expression and protein secretion as well as phosphorylation of JNK. Pretreatment of HBEpCs with 1 μM LPA for 6 h attenuated IL-13- but not IL-4-induced phosphorylation of STAT6. Transfection of HBEpCs with IL-13Rα2 small interference RNA blocked the effect of LPA on IL-13-induced phosphorylation of STAT6. Furthermore, pretreatment with LPA (1 μM, 6 h) attenuated IL-13-induced eotaxin-1 and SOCS-1 gene expression. These results demonstrate that LPA induces IL-13Rα2 expression and release via PLD and JNK/AP-1 signal transduction and that pretreatment with LPA down-regulates IL-13 signaling in HBEpCs. Our data suggest a novel mechanism of regulation of IL-13Rα2 and IL-13 signaling that may be of physiological relevance to airway inflammation and remodeling.

Original languageEnglish (US)
Pages (from-to)10172-10179
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number14
DOIs
StatePublished - Apr 6 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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