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J. Biol. Chem., Vol. 279, Issue 39, 41085-41094, September 24, 2004

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Protein Kinase C Mediates Lysophosphatidic Acid-induced NF-B Activation and Interleukin-8 Secretion in Human Bronchial Epithelial Cells^*

Rhett Cummings, Yutong Zhao, David Jacoby, E. William Spannhake¶, Motoi Ohba||, Joe G. N. Garcia, Tonya Watkins, Donghong He, Bahman Saatian, and Viswanathan Natarajan**

From the Division of Pulmonary and Critical Care Medicine and the Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, the Department of Medicine, Oregon Health and Science University, Portland, Oregon 97239, the ^¶Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205, and the ^||Institute of Molecular Oncology, Showa University, Tokyo 142-8555, Japan

Lysophosphatidic acid (LPA), a potent bioactive lipid, elicits many of its biological actions via the specific G-protein-coupled receptors LPA₁, LPA₂, LPA₃, and LPA₄. Recently, we have shown that LPA-induced transactivation of platelet-derived growth factor receptor- is regulated by phospholipase D₂ in human bronchial epithelial cells (HBEpCs) (Wang, L., Cummings, R. J., Zhao, Y., Kazlauskas, A., Sham, J., Morris, A., Brindley, D. N., Georas, S., and Natarajan, V. (2003) J. Biol. Chem. 278, 39931-39940). Here, we report that protein kinase C (PKC) mediates LPA-induced NF-B transcription and interleukin-8 (IL-8) secretion in HBEpCs. Treatment of HBEpCs with LPA increased both IL-8 gene and protein expression, which was coupled to G_i and G_12/13 proteins. LPA caused a marked activation of NF-B in HBEpCs as determined by IB phosphorylation and of NF-B nuclear translocation and a strong induction of NF-B promoter-mediated luciferase activity. Furthermore, LPA-activated PKC and the LPA-mediated activation of NF-B and IL-8 production were attenuated by overexpression of dominant-negative PKC and rottlerin. Intratracheal administration of LPA in mice resulted in elevated levels of macrophage inflammatory protein-2, a murine homolog of IL-8, and an influx of neutrophils in the bronchoalveolar lavage fluid. These results demonstrate for the first time that LPA is a potent stimulator of IL-8 production in HBEpCs, which involves PKC/NF-B signaling pathways.

Received for publication, April 12, 2004 , and in revised form, July 7, 2004.

^* This work was supported by National Institutes of Health Grant HL71121 (to V. N.) and Grants HL54659 and HL61013 (to D. J.). 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.

^** To whom correspondence should be addressed: Dept. of Medicine, Div. of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, MFL 675, Center Tower, 5200 Eastern Ave., Baltimore, MD 21224. Tel.: 410-550-7748; Fax: 410-550-8571; E-mail: vnataraj{at}jhmi.edu.

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