Inhibition of IL-13 Signaling in Bronchial Epithelial Cells by LPA

Abstract

The cytokine interleukin-13 (IL-13), a Th2-associated cytokine, plays a role in the pathogenesis of bronchial asthma. IL-13 signals through its receptor, a heterodimer of IL-13 receptor α1 (IL-13Rα1) and IL-4 receptor α (IL-4Rα), to activate signal transducer and activator of transcription 6 (STAT6). Another receptor, IL-13Rα2, with higher affinity for IL-13 than that of IL-13Rα1, acts as a decoy receptor for IL-13, blocking its signaling. Phospholipid lysophosphatidic acid (LPA) has been detected in the lung and signals through G protein-coupled receptors to enhance production of epithelial chemokines. To investigate a role for LPA in airway modulation, Zhao et al . treated primary cultures of human bronchial epithelial cells (HBEpCs) with LPA for various time periods. Through real-time polymerase chain reaction and Western blotting analyses, the authors found that the abundance of mRNA and protein for IL-13Rα2, but not IL-13Rα1 or IL-4Rα, were increased and that IL-13Rα2 protein was secreted by the cells, with a peak production time after 6 hours of treatment. These effects were blocked if cells were pretreated with pertussis toxin, indicating that the effect of LPA on IL-13Rα2 production was mediated by G proteins of the G i family. Treatment of HBEpCs with LPA also blocked the ability of IL-13, but not IL-4, to activate STAT6. Studies with pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that LPA stimulation of IL-13Rα2 production was dependent on the activities of both c-Jun N-terminal kinase and phospholipase D. This study suggests that LPA functions to protect bronchial epithelium during airway inflammation in asthma. Y. Zhao, D. He, J. Zhao, L. Wang, A. R. Leff, E. W. Spannhake, S. Georas, V. Natarajan, Lysophosphatidic acid induces interleukin-13 (IL-13) receptor α2 expression and inhibits IL-13 signaling in primary human bronchial epithelial cells. J. Biol. Chem. 282 , 10172-10179 (2007). [Abstract] [Full Text]