PMID- 9920834
OWN - NLM
STAT- MEDLINE
DCOM- 19990218
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 93
IP  - 3
DP  - 1999 Feb 1
TI  - The MKK6/p38 stress kinase cascade is critical for tumor necrosis 
      factor-alpha-induced expression of monocyte-chemoattractant protein-1 in 
      endothelial cells.
PG  - 857-65
AB  - 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-alpha (TNF-alpha), 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-alpha-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-alpha-induced expression of 
      MCP-1. Consistent with that finding, expression of wild-type or constitutively 
      active MKK6 significantly enhanced the effect of limiting TNF-alpha 
      concentrations on MCP-1 synthesis. These data suggest a crucial role for the 
      MKK6/p38 stress kinase cascade in TNF-alpha-mediated endothelial MCP-1 
      expression.
FAU - Goebeler, M
AU  - Goebeler M
AD  - Klinik und Poliklinik fur Haut- und Geschlechtskrankheiten and Institut fur 
      Medizinische Strahlenkunde und Zellforschung (MSZ), Universitat Wurzburg, 
      Wurzburg, Germany.
FAU - Kilian, K
AU  - Kilian K
FAU - Gillitzer, R
AU  - Gillitzer R
FAU - Kunz, M
AU  - Kunz M
FAU - Yoshimura, T
AU  - Yoshimura T
FAU - Brocker, E B
AU  - Brocker EB
FAU - Rapp, U R
AU  - Rapp UR
FAU - Ludwig, S
AU  - Ludwig S
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Chemokine CCL2)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Imidazoles)
RN  - 0 (Pyridines)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 6)
RN  - EC 2.7.12.2 (MAP2K6 protein, human)
RN  - OU13V1EYWQ (SB 203580)
RN  - PVX798P8GI (4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole)
SB  - IM
MH  - Calcium-Calmodulin-Dependent Protein Kinases/antagonists & 
      inhibitors/genetics/metabolism/*physiology
MH  - Cells, Cultured
MH  - Chemokine CCL2/*biosynthesis/genetics
MH  - Endothelium, Vascular/cytology/*metabolism
MH  - Enzyme Activation
MH  - Enzyme Inhibitors/pharmacology
MH  - Gene Expression Regulation/*drug effects
MH  - Humans
MH  - Imidazoles/pharmacology
MH  - JNK Mitogen-Activated Protein Kinases
MH  - MAP Kinase Kinase 6
MH  - Mitogen-Activated Protein Kinase 3
MH  - *Mitogen-Activated Protein Kinases
MH  - Multigene Family
MH  - Pyridines/pharmacology
MH  - RNA, Messenger/biosynthesis
MH  - Recombinant Fusion Proteins/biosynthesis/physiology
MH  - Signal Transduction/*physiology
MH  - Stress, Physiological/*physiopathology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 1999/01/28 00:00
MHDA- 1999/01/28 00:01
CRDT- 1999/01/28 00:00
PHST- 1999/01/28 00:00 [pubmed]
PHST- 1999/01/28 00:01 [medline]
PHST- 1999/01/28 00:00 [entrez]
AID - S0006-4971(20)48800-7 [pii]
PST - ppublish
SO  - Blood. 1999 Feb 1;93(3):857-65.