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

91 Citations (Scopus)

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

Fingerprint

Interleukin-8
Protein Kinase C
Epithelial Cells
Chemical activation
G12-G13 GTP-Binding Protein alpha Subunits
Chemokine CXCL2
lysophosphatidic acid
Platelet-Derived Growth Factor Receptors
Phosphorylation
Bronchoalveolar Lavage Fluid
Transcription
G-Protein-Coupled Receptors
Luciferases
Transcriptional Activation
Proteins
Neutrophils
Lipids
Gene Expression
Fluids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Protein kinase Cδ mediates lysophosphatidic acid-induced NF-κB activation and interleukin-8 secretion in human bronchial epithelial cells. / Cummings, Rhett; Zhao, Yutong; Jacoby, David; Spannhake, E. William; Ohba, Motoi; Garcia, Joe G N; Watkins, Tonya; He, Donghong; Saatian, Bahman; Natarajan, Viswanathan.

In: Journal of Biological Chemistry, Vol. 279, No. 39, 24.09.2004, p. 41085-41094.

Research output: Contribution to journalArticle

Cummings, R, Zhao, Y, Jacoby, D, Spannhake, EW, Ohba, M, Garcia, JGN, 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, vol. 279, no. 39, pp. 41085-41094. https://doi.org/10.1074/jbc.M404045200
Cummings, Rhett ; Zhao, Yutong ; Jacoby, David ; Spannhake, E. William ; Ohba, Motoi ; Garcia, Joe G N ; Watkins, Tonya ; He, Donghong ; Saatian, Bahman ; Natarajan, Viswanathan. / Protein kinase Cδ mediates lysophosphatidic acid-induced NF-κB activation and interleukin-8 secretion in human bronchial epithelial cells. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 39. pp. 41085-41094.
@article{c108729cd581439c86ffdafdda986680,
title = "Protein kinase Cδ mediates lysophosphatidic acid-induced NF-κB activation and interleukin-8 secretion in human bronchial epithelial cells",
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.",
author = "Rhett Cummings and Yutong Zhao and David Jacoby and Spannhake, {E. William} and Motoi Ohba and Garcia, {Joe G N} and Tonya Watkins and Donghong He and Bahman Saatian and Viswanathan Natarajan",
year = "2004",
month = "9",
day = "24",
doi = "10.1074/jbc.M404045200",
language = "English (US)",
volume = "279",
pages = "41085--41094",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "39",

}

TY - JOUR

T1 - Protein kinase Cδ mediates lysophosphatidic acid-induced NF-κB activation and interleukin-8 secretion in human bronchial epithelial cells

AU - Cummings, Rhett

AU - Zhao, Yutong

AU - Jacoby, David

AU - Spannhake, E. William

AU - Ohba, Motoi

AU - Garcia, Joe G N

AU - Watkins, Tonya

AU - He, Donghong

AU - Saatian, Bahman

AU - Natarajan, Viswanathan

PY - 2004/9/24

Y1 - 2004/9/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=4644335035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4644335035&partnerID=8YFLogxK

U2 - 10.1074/jbc.M404045200

DO - 10.1074/jbc.M404045200

M3 - Article

C2 - 15280372

AN - SCOPUS:4644335035

VL - 279

SP - 41085

EP - 41094

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 39

ER -