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

Cytokine. 2002 May 21;18(4):206-13. doi: 10.1006/cyto.2002.1034.


Interleukin (IL)-1 modulates the expression of various genes in normal and tumor cells. We investigated the molecular mechanisms underlying IL-1beta-induced expression of IL-8 mRNA and protein in human vascular smooth muscle cells (hVSMCs). P38 mitogen-activated protein kinase (MAPK) was activated after 5min of IL-1beta treatment, whereas the extracellular signal-regulated kinases, the c-jun amino-terminal kinases, and protein kinase B/Akt were not activated by IL-1beta. IL-1beta induced activation of a full-length IL-8 promoter-reporter construct. Deletional mutagenesis localized the IL-1beta-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-kappaB (NF-kappaB), 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-1beta increased AP-1 and NF-kappaB DNA-binding activities in a time-dependent manner. SB203580, a specific P38 MAPK inhibitor, partially blocked IL-1beta induction of IL-8 mRNA, IL-8 promoter activity, and AP-1 nuclear extract binding but not NF-kappaB DNA binding. Our data demonstrate that AP-1 and NF-kappaB are essential transcription factors for IL-1beta-induced IL-8 gene expression in hVSMCs. P38 MAPK is involved in inducing IL-8 gene transcription via AP-1 activation in hVSMCs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Blotting, Northern
  • Blotting, Western
  • Cell Division
  • Cell Nucleus / metabolism
  • Cell Survival
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular / cytology*
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Interleukin-1 / metabolism
  • Interleukin-8 / metabolism*
  • Mitogen-Activated Protein Kinases / physiology*
  • Mutagenesis, Site-Directed
  • Myocytes, Smooth Muscle / cytology*
  • NF-kappa B / metabolism*
  • Neovascularization, Physiologic
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Structure, Tertiary
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Transcription Factor AP-1 / metabolism*
  • Transcription, Genetic
  • p38 Mitogen-Activated Protein Kinases


  • Enzyme Inhibitors
  • Interleukin-1
  • Interleukin-8
  • NF-kappa B
  • RNA, Messenger
  • Transcription Factor AP-1
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases