The MKK6/p38 Stress Kinase Cascade Is Critical for Tumor Necrosis Factor-–Induced Expression of Monocyte-Chemoattractant Protein-1 in Endothelial Cells

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  • Matthias Goebeler
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.
  • Karin Kilian
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.
  • Reinhard Gillitzer
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.
  • Manfred Kunz
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.
  • Teizo Yoshimura
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.
  • Eva-B. Bröcker
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.
  • Ulf R. Rapp
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.
  • Stephan Ludwig
    From the Klinik und Poliklinik für Haut- und Geschlechtskrankheiten and Institut für Medizinische Strahlenkunde und Zellforschung (MSZ), Universität Würzburg, Würzburg, Germany; and the Immunopathology Section, Laboratory of Immunobiology, National Cancer Institute-Frederick, Frederick, MD.

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<jats:title>Abstract</jats:title><jats:p>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- (TNF-), 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-–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-–induced expression of MCP-1. Consistent with that finding, expression of wild-type or constitutively active MKK6 significantly enhanced the effect of limiting TNF- concentrations on MCP-1 synthesis. These data suggest a crucial role for the MKK6/p38 stress kinase cascade in TNF-–mediated endothelial MCP-1 expression.</jats:p>

収録刊行物

  • Blood

    Blood 93 (3), 857-865, 1999-02-01

    American Society of Hematology

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