Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 282, Issue 14, Pages 10172-10179Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M611210200
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- NHLBI NIH HHS [R01 HL071152-02, HL71152, R01 HL071152] Funding Source: Medline
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Interleukin-13 (IL-13), a Th2 cytokine, plays a pivotal role in pathogenesis of bronchial asthma via IL-13 receptor alpha 1 ( IL-13R alpha 1) and IL-4 receptor alpha(IL-4R alpha). Recent studies show that a decoy receptor for IL-13, namely IL-13R alpha 2, mitigates IL-13 signaling and function. This study provides evidence for regulation of IL-13R alpha 2 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-13R alpha 2 gene expression without altering the mRNA levels of IL-13R alpha 1 and IL-4R alpha. 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-13R alpha 2 gene expression and secretion of soluble IL-13R alpha 2. Overexpression of catalytically inactive mutants of phospholipase D(PLD) 1 or 2 attenuated LPA-induced IL-13R alpha 2 gene expression and protein secretion as well as phosphorylation of JNK. Pretreatment of HBEpCs with 1 mu m LPA for 6 h attenuated IL-13 but not IL-4 induced phosphorylation of STAT6. Transfection of HBEpCs with IL-13R alpha 2 small interference RNA blocked the effect of LPA on IL-13-induced phosphorylation of STAT6. Furthermore, pretreatment with LPA (1 mu m, 6 h) attenuated IL-13-induced eotaxin-1 and SOCS-1 gene expression. These results demonstrate that LPA induces IL-13R alpha 2 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-13R alpha 2 and IL-13 signaling that may be of physiological relevance to airway inflammation and remodeling.
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