The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-α-induced expression of monocyte-chemoattractant protein-1 in endothelial cells

Matthias Goebeler, Karin Kilian, Reinhard Gillitzer, Manfred Kunz, Teizo Yoshimura, Eva B. Bröcker, Ulf R. Rapp, Stephan Ludwig

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Monocyte chemoattractant protein-1 (MCP-1), a member of the C-C subfamily of chemokines, is important for the local recruitment of leukocytes to sites of inflammatory challenge. Here, we investigated endothelial signaling pathways involving members of the mitogen-activated protein (MAP) kinase superfamily and studied their role for MCP-1 expression in endothelium. We show that tumor necrosis factor-α (TNF-α), a potent inflammatory activator of endothelium, leads to activation of MAP kinases ERK, p38, and JNK in human umbilical vein endothelial cells (HUVEC). Contribution of MAP kinase pathways to TNF-α-induced synthesis of endothelial MCP-1 was then studied by pharmacologic inhibition and transient expression of dominant negative or constitutively active kinase mutants using flow cytometry, Northern blot, and luciferase reporter gene assays. Inhibition of Raf/MEK/ERK or SEK/JNK pathways had no significant effect on MCP-1 levels, whereas blocking the MKK6/p38 pathway by p38 inhibitors SB203580 or SB202190 or by a dominant negative mutant of MKK6, the upstream activator of p38, strongly inhibited TNF-α-induced expression of MCP-1. Consistent with that finding, expression of wild-type or constitutively active MKK6 significantly enhanced the effect of limiting TNF-α concentrations on MCP-1 synthesis. These data suggest a crucial role for the MKK6/p38 stress kinase cascade in TNF-α-mediated endothelial MCP-1 expression.

Original languageEnglish
Pages (from-to)857-865
Number of pages9
JournalBlood
Volume93
Issue number3
Publication statusPublished - Feb 1 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Goebeler, M., Kilian, K., Gillitzer, R., Kunz, M., Yoshimura, T., Bröcker, E. B., Rapp, U. R., & Ludwig, S. (1999). The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-α-induced expression of monocyte-chemoattractant protein-1 in endothelial cells. Blood, 93(3), 857-865.