79 LYSOPHOSPHATIDIC ACID INDUCES INTERLEUKIN-13 RECEPTOR a2 EXPRESSION AND SECRETION AND DOWN-REGULATES INTERLEUKIN-13 SIGNALING IN HUMAN BRONCHIAL EPITHELIAL PRIMARY CELLS

RationaleIL-13, a Th2 cytokine, plays pivotal role in pathogenesis of bronchial asthma by inducing airway hyperresponsiveness (AHR), mucus hyperproduction, and submucosal thickness. IL-13 mediates airway responses via IL-13 receptor a1 and IL-4 receptor. Recent studies show that a decoy receptor for IL-13, namely IL-13 receptor a2 (IL-13R a2), mitigates IL-13 signaling and function. However, the mechanism(s) of regulation of IL-13R a2 generation and its role in IL-13 signal transduction is not clear. This study provides evidence for regulation of IL-13R a2 production and secretion and IL-13-dependent STAT6 signaling by lysophosphatidic acid (LPA) in human primary bronchial epithelial cells (HBEpCs).Methods/ResultsLPA (1 μM) treatment of HBEpCs, in a time-dependent fashion, increased IL-13R a2 gene expression without altering the mRNA levels of IL-13 R a1 and IL-4 R. Furthermore, LPA (1 μM) stimulated secretion of IL-13 R a2 into the cell culture medium as evidenced by Western blotting with anti-IL-13 Ra2 antibody. Pretreatment with PTx (100 ng/mL, 3 hours), or JNK inhibitor, or c-jun siRNA attenuated LPA-induced IL-13R a2 secretion. Overexpression of phospholipase D (PLD) 1 or 2 catalytically inactive mutants or pretreatment with 1-butanol, but not 3-butanol, attenuated LPA-induced IL-13R a2 secretion as well as phosphorylation of JNK. Pretreatment of HBEpCs with 1 μM of LPA for 6 hours attenuated IL-13-induced phosphorylation of STAT6 but not the IL-4-induced phosphorylation of STAT6. In addition, replacement of media from LPA- (1 μM, 6 hours) challenged cells with fresh media or transfection with IL-13R a2 siRNA reverted IL-13-induced phosphorylation of STAT6.ConclusionsWe show here that LPA induces IL-13R a2 expression and secretion via PLD and JNK/AP-1 signaling and that pretreatment with LPA down-regulates IL-13 signaling in HBEpCs. These data suggest a novel mechanism of regulation of IL-13R a2 and IL-13 signaling that may be of physiological relevance to asthma and airway remodeling.Supported by NIH grant HL 71152 to V.N.