Lysophosphatidic acid induces interleukin-13 (IL-13) receptor alpha2 expression and inhibits IL-13 signaling in primary human bronchial epithelial cells.
Interleukin-13 (IL-13), a Th2 cytokine, plays a pivotal role in pathogenesis of bronchial asthma via IL-13 receptor alpha1 (IL-13Ralpha1) and IL-4 receptor alpha (IL-4Ralpha). Recent studies show that a decoy receptor for IL-13, namely IL-13Ralpha2, mitigates IL-13 signaling and function. This study provides evidence for regulation of IL-13Ralpha2 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-13Ralpha2 gene expression without altering the mRNA levels of IL-13Ralpha1 and IL-4Ralpha. 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-13Ralpha2 gene expression and secretion of soluble IL-13Ralpha2. Overexpression of catalytically inactive mutants of phospholipase D (PLD) 1 or 2 attenuated LPA-induced IL-13Ralpha2 gene expression and protein secretion as well as phosphorylation of JNK. Pretreatment of HBEpCs with 1 microM LPA for 6 h attenuated IL-13-but not IL-4-induced phosphorylation of STAT6. Transfection of HBEpCs with IL-13Ralpha2 small interference RNA blocked the effect of LPA on IL-13-induced phosphorylation of STAT6. Furthermore, pretreatment with LPA (1 microM, 6 h) attenuated IL-13-induced eotaxin-1 and SOCS-1 gene expression. These results demonstrate that LPA induces IL-13Ralpha2 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-13Ralpha2 and IL-13 signaling that may be of physiological relevance to airway inflammation and remodeling.
Zhao
Yutong
Y
Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois 60637, USA. yzhao@medicine.bsd.uchicago.edu
He
Donghong
D
Zhao
Jing
J
Wang
Lixin
L
Leff
Alan R
AR
Spannhake
Ernst Wm
EW
Georas
Steve
S
Natarajan
Viswanathan
V
D001249:Asthma / Q000378:metabolism; D001980:Bronchi / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism*; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000096:biosynthesis*; D008246:Lysophospholipids / Q000494:pharmacology*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D018793:Interleukin-13; D053663:Interleukin-13 Receptor alpha2 Subunit; D008246:Lysophospholipids; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D019948:Receptors, Interleukin-4; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D018808:Transcription Factor AP-1; D037342:Pertussis Toxin; D048670:MAP Kinase Kinase 4; C032881:lysophosphatidic acid