Published online before print January 15, 2009

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(American Journal of Pathology. 2009;174:1264-1279.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080160

Lysophosphatidic Acid Induces vβ6 Integrin-Mediated TGF-β Activation via the LPA2 Receptor and the Small G Protein G_q

Ming Yan Xu^*, Joanne Porte^*, Alan J. Knox^*, Paul H. Weinreb, Toby M. Maher, Shelia M. Violette, Robin J. McAnulty, Dean Sheppard and Gisli Jenkins^*

From the Centre for Respiratory Research,^* the University of Nottingham, United Kingdom; the Lung Biology Center, University of California at San Francisco, San Francisco, California; Biogen Idec, Cambridge, Massachusetts; and the Centre for Respiratory Research, University College London, United Kingdom

Activation of latent transforming growth factor β (TGF-β) by vβ6 integrin is critical in the pathogenesis of lung injury and fibrosis. We have previously demonstrated that the stimulation of protease activated receptor 1 promotes vβ6 integrin-mediated TGF-β activation via RhoA, which is known to modulate cell contraction. However, whether other G protein-coupled receptors can also induce vβ6 integrin-mediated TGF-β activation is unknown; in addition, the vβ6 integrin signaling pathway has not yet been fully characterized. In this study, we show that lysophosphatidic acid (LPA) induces vβ6-mediated TGF-β activation in human epithelial cells via both RhoA and Rho kinase. Furthermore, we demonstrate that LPA-induced vβ6 integrin-mediated TGF-β activity is mediated via the LPA2 receptor, which signals via G_q. Finally, we show that the expression levels of both the LPA2 receptor and vβ6 integrin are up-regulated and are spatially and temporally associated following bleomycin-induced lung injury. Furthermore, both the LPA2 receptor and vβ6 integrin are up-regulated in the overlying epithelial areas of fibrosis in patients with usual interstitial pneumonia. These studies demonstrate that LPA induces vβ6 integrin-mediated TGF-β activation in epithelial cells via LPA2, G_q, RhoA, and Rho kinase, and that this pathway might be clinically relevant to the development of lung injury and fibrosis.