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79 LYSOPHOSPHATIDIC ACID INDUCES INTERLEUKIN-13 RECEPTOR a2 EXPRESSION AND SECRETION AND DOWN-REGULATES INTERLEUKIN-13 SIGNALING IN HUMAN BRONCHIAL EPITHELIAL PRIMARY CELLS.
  1. Y. Zhao1,
  2. D. He1,
  3. J. Zhao1,
  4. E. W. Spannhake2,
  5. A. Leff1,
  6. V. Natarajan1
  1. 1Department of Medicine, The University of Chicago, Chicago, IL
  2. 2Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD

Abstract

Rationale IL-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/Results LPA (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.

Conclusions We 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.

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