Protein kinase Cδ mediates lysophosphatidic acid-induced NF-κB 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, Viswanathan Natarajan

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

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-β is regulated by pliospholipase 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 Cδ (PKCδ) mediates LPA-induced NF-κB 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 Gi and G 12/13 proteins. LPA caused a marked activation of NF-κB in HBEpCs as determined by IκB phosphorylation and of NF-κB nuclear translocation and a strong induction of NF-κB promoter-mediated luciferase activity. Furthermore, LPA-activated PKCδ and the LPA-mediated activation of NF-κB and IL-8 production were attenuated by overexpression of dominant-negative PKCδ 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 PKCδ/NF-κB signaling pathways.

Original languageEnglish (US)
Pages (from-to)41085-41094
Number of pages10
JournalJournal of Biological Chemistry
Volume279
Issue number39
DOIs
StatePublished - Sep 24 2004

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Cummings, R., Zhao, Y., Jacoby, D., Spannhake, E. W., Ohba, M., Garcia, J. G. N., Watkins, T., He, D., Saatian, B., & Natarajan, V. (2004). Protein kinase Cδ mediates lysophosphatidic acid-induced NF-κB activation and interleukin-8 secretion in human bronchial epithelial cells. Journal of Biological Chemistry, 279(39), 41085-41094. https://doi.org/10.1074/jbc.M404045200