Protein kinase C-delta regulates thrombin-induced ICAM-1 gene expression in endothelial cells via activation of p38 mitogen-activated protein kinase

Mol Cell Biol. 2001 Aug;21(16):5554-65. doi: 10.1128/MCB.21.16.5554-5565.2001.


The procoagulant thrombin promotes the adhesion of polymorphonuclear leukocytes to endothelial cells by a mechanism involving expression of intercellular adhesion molecule 1 (ICAM-1) via an NF-kappaB-dependent pathway. We now provide evidence that protein kinase C-delta (PKC-delta) and the p38 mitogen-activated protein (MAP) kinase pathway play a critical role in the mechanism of thrombin-induced ICAM-1 gene expression in endothelial cells. We observed the phosphorylation of PKC-delta and p38 MAP kinase within 1 min after thrombin challenge of human umbilical vein endothelial cells. Pretreatment of these cells with the PKC-delta inhibitor rottlerin prevented the thrombin-induced phosphorylation of p38 MAP kinase, suggesting that p38 MAP kinase signals downstream of PKC-delta. Inhibition of PKC-delta or p38 MAP kinase by pharmacological and genetic approaches markedly decreased the thrombin-induced NF-kappaB activity and resultant ICAM-1 expression. The effects of PKC-delta inhibition were secondary to inhibition of IKKbeta activation and of subsequent NF-kappaB binding to the ICAM-1 promoter. The effects of p38 MAP kinase inhibition occurred downstream of IkappaBalpha degradation without affecting the DNA binding function of nuclear NF-kappaB. Thus, PKC-delta signals thrombin-induced ICAM-1 gene transcription by a dual mechanism involving activation of IKKbeta, which mediates NF-kappaB binding to the ICAM-1 promoter, and p38 MAP kinase, which enhances transactivation potential of the bound NF-kappaB p65 (RelA).

Publication types

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

MeSH terms

  • Cells, Cultured
  • Endothelium, Vascular / physiology*
  • Enzyme Activation
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Adhesion Molecule-1 / genetics*
  • Isoenzymes / physiology*
  • Mitogen-Activated Protein Kinases / physiology*
  • NF-kappa B / physiology
  • Protein Kinase C / physiology*
  • Protein Kinase C-delta
  • Signal Transduction / drug effects
  • Thrombin / pharmacology
  • Thrombin / physiology*
  • p38 Mitogen-Activated Protein Kinases


  • Isoenzymes
  • NF-kappa B
  • Intercellular Adhesion Molecule-1
  • PRKCD protein, human
  • Protein Kinase C
  • Protein Kinase C-delta
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Thrombin