Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells

Bahman Saatian, Yutong Zhao, Donghong He, Steve N. Georas, Tonya Watkins, Ernst W Spannhake, Viswanathan Natarajan

Research output: Contribution to journalArticle

Abstract

HBEpCs (human bronchial epithelial cells) contribute to airway inflammation by secreting a variety of cytokines and chemokines in response to allergens, pathogens, viruses and environmental toxins and pollutants. The potent neutrophil chemoattractant, IL-8 (interleukin-8), is a major cytokine secreted by HBEpCs. We have recently demonstrated that LPA (lysophosphatidic acid) stimulated IL-8 production in HBEpCs via protein kinase C δ dependent signal transduction. However, mechanisms of IL-8 expression and secretion are complex and involve multiple protein kinases and transcriptional factors. The present study was undertaken to investigate MAPK (mitogen-activated protein kinase) signalling in the transcriptional regulation of IL-8 expression and secretion in HBEpCs. Exposure of HBEpCs to LPA (1 μM) enhanced expression and secretion of IL-8 by 5-8-fold and stimulated threonine/tyrosine phosphorylation of ERK (extracellular-signal-regulated kinase), p38 MAPK and JNK (c-Jun N-terminal kinase). The LPA-induced secretion of IL-8 was blocked by the p38 MAPK inhibitor SB203580, by p38 MAPK siRNA (small interfering RNA), and by the JNK inhibitor JNKi II, but not by the MEK (MAPK/ERK kinase) inhibitor, PD98059. LPA enhanced the transcriptional activity of the IL-8 gene; that effect relied on activation of the transcriptional factors NF-κB (nuclear factor κB) and AP-1 (activator protein-1). Furthermore, SB203580 attenuated LPA-dependent phosphorylation of IκB (inhibitory κB), NF-κB and phospho-p38 translocation to the nucleus, NF-κB transcription and IL-8 promoter-mediated luciferase reporter activity, without affecting the JNK pathway and AP-1 transcription. Similarly, JNKi II only blocked LPA-mediated phosphorylation of JNK and c-Jun, AP-1 transcription and IL-8 promoter-mediated luciferase reporter activity, without blocking p38 MAPK-dependent NF-κB transcription. Additionally, siRNA for LPA 1-3 receptors partially blocked LPA-induced IL-8 production and activation of MAPKs. The LPA1 and LPA3 receptors, as compared with LPA2, were most efficient in transducing LPA-mediated IL-8 production. These results show an independent role for p38 MAPK and JNK in LPA-induced IL-8 expression and secretion via NF-κB and AP-1 transcription respectively in HBEpCs.

Original languageEnglish (US)
Pages (from-to)657-668
Number of pages12
JournalBiochemical Journal
Volume393
Issue number3
DOIs
StatePublished - Feb 1 2006

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JNK Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
Interleukin-8
Epithelial Cells
Transcription
Transcription Factor AP-1
Phosphorylation
Lysophosphatidic Acid Receptors
Extracellular Signal-Regulated MAP Kinases
Mitogen-Activated Protein Kinases
Luciferases
Small Interfering RNA
lysophosphatidic acid
Chemical activation
Proto-Oncogene Proteins c-jun
Cytokines
Environmental Pollutants
Signal transduction
Chemotactic Factors
Interleukin-5

Keywords

  • AP-1
  • Interleukin-8
  • JNK
  • Lysophosphatidic acid
  • NFκB
  • p38 MAPK

ASJC Scopus subject areas

  • Biochemistry

Cite this

Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells. / Saatian, Bahman; Zhao, Yutong; He, Donghong; Georas, Steve N.; Watkins, Tonya; Spannhake, Ernst W; Natarajan, Viswanathan.

In: Biochemical Journal, Vol. 393, No. 3, 01.02.2006, p. 657-668.

Research output: Contribution to journalArticle

Saatian, Bahman ; Zhao, Yutong ; He, Donghong ; Georas, Steve N. ; Watkins, Tonya ; Spannhake, Ernst W ; Natarajan, Viswanathan. / Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells. In: Biochemical Journal. 2006 ; Vol. 393, No. 3. pp. 657-668.
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