Role of P38 MAPK, AP-1, and NF-κb in interleukin-1β-induced IL-8 expression in human vascular smooth muscle cells

Young D. Jung, Fan Fan, David J. McConkey, Marina E. Jean, Wenbiao Liu, Niels Reinmuth, Oliver Stoeltzing, Syed A. Ahmad, Alexander A. Parikh, Naofumi Mukaida, Lee M. Ellis

Research output: Contribution to journalArticle

Abstract

Interleukin (IL)-1 modulates the expression of various genes in normal and tumor cells. We investigated the molecular mechanisms underlying IL-1β-induced expression of IL-8 mRNA and protein in human vascular smooth muscle cells (hVSMCs). P38 mitogen-activated protein kinase (MAPK) was activated after 5 min of IL-1β treatment, whereas the extracellular signal-regulated kinases, the c-jun amino-terminal kinases, and protein kinase B/Akt were not activated by IL-1β. IL-1β induced activation of a full-length IL-8 promoter-reporter construct. Deletional mutagenesis localized the IL-1β-responsive domains to two regions (- 133 to - 98 and - 85 to - 50) that contain consensus binding sites for activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), respectively. Site-directed mutagenesis of the 133-bp minimal promoter confirmed that these sites were required for promoter activity. Electrophoretic mobility shift assays confirmed that IL-1β increased AP-1 and NF-κB DNA-binding activities in a time-dependent manner. SB203580, a specific P38 MAPK inhibitor, partially blocked IL-1β induction of IL-8 mRNA, IL-8 promoter activity, and AP-1 nuclear extract binding but not NF-κB DNA binding. Our data demonstrate that AP-1 and NF-κB are essential transcription factors for IL-1β-induced IL-8 gene expression in hVSMCs. P38 MAPK is involved in inducing IL-8 gene transcription via AP-1 activation in hVSMCs.

Original languageEnglish (US)
Pages (from-to)206-213
Number of pages8
JournalCytokine
Volume18
Issue number4
DOIs
StatePublished - May 2002
Externally publishedYes

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Keywords

  • AP-1
  • Interleukin-1 beta
  • Interleukin-8
  • Mitogen-activated protein kinase
  • NF-kappa B

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Biochemistry
  • Hematology
  • Molecular Biology

Cite this

Jung, Y. D., Fan, F., McConkey, D. J., Jean, M. E., Liu, W., Reinmuth, N., Stoeltzing, O., Ahmad, S. A., Parikh, A. A., Mukaida, N., & Ellis, L. M. (2002). Role of P38 MAPK, AP-1, and NF-κb in interleukin-1β-induced IL-8 expression in human vascular smooth muscle cells. Cytokine, 18(4), 206-213. https://doi.org/10.1006/cyto.2002.1034