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J. Biol. Chem., Vol. 282, Issue 14, 10172-10179, April 6, 2007

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Lysophosphatidic Acid Induces Interleukin-13 (IL-13) Receptor 2 Expression and Inhibits IL-13 Signaling in Primary Human Bronchial Epithelial Cells^*

Yutong Zhao¹, Donghong He, Jing Zhao, Lixin Wang, Alan R. Leff, Ernst Wm. Spannhake^¶, Steve Georas^||, and Viswanathan Natarajan

From the Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois 60637, Department of Gene Technology, Berlex Bioscience, Richmond, California 94806, ^¶Department of Environmental Health Sciences, Bloomberg School of Public Health, The Johns Hopkins University, Baltimore, Maryland 21205, and ^||Division of Pulmonary and Critical Care, Department of Medicine, University of Rochester, Rochester, New York 14627

Interleukin-13 (IL-13), a Th2 cytokine, plays a pivotal role in pathogenesis of bronchial asthma via IL-13 receptor 1 (IL-13R1) and IL-4 receptor (IL-4R). Recent studies show that a decoy receptor for IL-13, namely IL-13R2, mitigates IL-13 signaling and function. This study provides evidence for regulation of IL-13R2 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 at imedependent fashion increased IL-13R2 gene expression without altering the mRNA levels of IL-13R1 and IL-4R. 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-13R2 gene expression and secretion of soluble IL-13R2. Overexpression of catalytically inactive mutants of phospholipase D (PLD) 1 or 2 attenuated LPA-induced IL-13R2 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-13R2 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-13R2 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-13R2 and IL-13 signaling that may be of physiological relevance to airway inflammation and remodeling.

Received for publication, December 6, 2006 , and in revised form, January 17, 2007.

^* This work was supported by National Institutes of Health Grant HL71152 (to V. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Medicine, The University of Chicago, Center for Integrative Science Bldg., Rm. W403M, 929 East 57th St., Chicago, IL 60637. Tel.: 773-834-2385; Fax: 773-834-2687; E-mail: yzhao{at}medicine.bsd.uchicago.edu.

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