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

139 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

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Chemokine CCL2
Endothelial cells
Phosphotransferases
Endothelial Cells
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinases
Endothelium
CC Chemokines
Flow cytometry
MAP Kinase Signaling System
Mitogen-Activated Protein Kinase Kinases
Human Umbilical Vein Endothelial Cells
p38 Mitogen-Activated Protein Kinases
Luciferases
Reporter Genes
Chemokines
Northern Blotting
Assays
Flow Cytometry
Leukocytes

ASJC Scopus subject areas

  • Hematology

Cite this

The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-α-induced expression of monocyte-chemoattractant protein-1 in endothelial cells. / Goebeler, Matthias; Kilian, Karin; Gillitzer, Reinhard; Kunz, Manfred; Yoshimura, Teizo; Bröcker, Eva B.; Rapp, Ulf R.; Ludwig, Stephan.

In: Blood, Vol. 93, No. 3, 01.02.1999, p. 857-865.

Research output: Contribution to journalArticle

Goebeler, M, Kilian, K, Gillitzer, R, Kunz, M, Yoshimura, T, Bröcker, EB, Rapp, UR & 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, vol. 93, no. 3, pp. 857-865.
Goebeler, Matthias ; Kilian, Karin ; Gillitzer, Reinhard ; Kunz, Manfred ; Yoshimura, Teizo ; Bröcker, Eva B. ; Rapp, Ulf R. ; Ludwig, Stephan. / The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-α-induced expression of monocyte-chemoattractant protein-1 in endothelial cells. In: Blood. 1999 ; Vol. 93, No. 3. pp. 857-865.
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