PMID- 11133741
OWN - NLM
STAT- MEDLINE
DCOM- 20010215
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 97
IP  - 1
DP  - 2001 Jan 1
TI  - Multiple signaling pathways regulate NF-kappaB-dependent transcription of the 
      monocyte chemoattractant protein-1 gene in primary endothelial cells.
PG  - 46-55
AB  - The cytokine-induced C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is 
      an important regulator of leukocyte recruitment to sites of inflammatory 
      challenge. Here, it is demonstrated that the widely distributed contact hapten 
      NiCl(2), like tumor necrosis factor alpha (TNFalpha), induces 
      monocyte-chemoattractant activity in primary human endothelial cells via 
      induction of MCP-1. NiCl(2) rapidly activated mitogen-activated protein (MAP) 
      kinase p38, and inhibition of p38 partially blocked NiCl(2)-induced MCP-1 
      messenger RNA and protein expression. Both NiCl(2)- and TNFalpha-induced MCP-1 
      synthesis was sensitive to D609, an inhibitor of phosphatidylcholine-dependent 
      phospholipase C (PC-PLC). NiCl(2)-induced MCP-1 synthesis required activation of 
      NF-kappaB since mutation of NF-kappaB-binding sites in the promoter resulted in 
      complete loss of inducible promoter activity. Consistent with that finding, 
      stimulation with NiCl(2) or TNFalpha activated IkappaB kinase-beta (IKKbeta), and 
      transient transfection of dominant-negative IKKbeta strongly inhibited NiCl(2)- 
      and TNFalpha-induced MCP-1 expression. However, D609 and the specific p38 
      inhibitor SB202190 did not affect NiCl(2)- and TNFalpha-induced IKKbeta 
      activation, NF-kappaB DNA-binding activity, or transcriptional activity of a 
      Gal4p65 fusion protein. This indicates that p38- and PC-PLC-dependent pathways 
      directly regulate the transcriptional activity of NF-kappaB factors in the 
      transcriptional complex. Consistent with that, inhibition of p38 blocked enhanced 
      transcriptional activity induced by the transcriptional coactivator p300. Thus, 
      it was concluded that at least 3 independent pathways regulate MCP-1 expression 
      in endothelial cells. Its induction requires activation of the 
      IKKbeta/IkappaBalpha/NF-kappaB signaling pathway, resulting in nuclear 
      accumulation of p65 and subsequent recruitment of cofactors. Proper assembly and 
      activity of this transcriptional complex is further modulated by the p38 MAP 
      kinase cascade and a PC-PLC-dependent pathway.
FAU - Goebeler, M
AU  - Goebeler M
AD  - Klinik und Poliklinik fur Hautkrankheiten and the Institut fur Medizinische 
      Strahlenkunde und Zellforschung, University of Wurzburg, Wurzburg, Germany. 
      goebeler-m.derma@mail.uni-wuerzburg.de
FAU - Gillitzer, R
AU  - Gillitzer R
FAU - Kilian, K
AU  - Kilian K
FAU - Utzel, K
AU  - Utzel K
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 (Haptens)
RN  - 0 (NF-kappa B)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Trans-Activators)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 696BNE976J (nickel chloride)
RN  - 7OV03QG267 (Nickel)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - EC 3.1.4.- (Type C Phospholipases)
SB  - IM
MH  - Chemokine CCL2/*biosynthesis/*genetics
MH  - Endothelium, Vascular/cytology/*metabolism/physiology
MH  - Gene Expression Regulation/drug effects
MH  - Haptens
MH  - Humans
MH  - Mitogen-Activated Protein Kinases/physiology
MH  - NF-kappa B/*pharmacology
MH  - Nickel/pharmacology
MH  - Nuclear Proteins/antagonists & inhibitors/drug effects/metabolism
MH  - Promoter Regions, Genetic/drug effects
MH  - RNA, Messenger/drug effects
MH  - Signal Transduction/physiology
MH  - Trans-Activators/antagonists & inhibitors/drug effects/metabolism
MH  - Transcription, Genetic/drug effects
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - Type C Phospholipases/physiology
MH  - Umbilical Veins/cytology
MH  - p38 Mitogen-Activated Protein Kinases
EDAT- 2001/01/03 11:00
MHDA- 2001/03/03 10:01
CRDT- 2001/01/03 11:00
PHST- 2001/01/03 11:00 [pubmed]
PHST- 2001/03/03 10:01 [medline]
PHST- 2001/01/03 11:00 [entrez]
AID - S0006-4971(20)48107-8 [pii]
AID - 10.1182/blood.v97.1.46 [doi]
PST - ppublish
SO  - Blood. 2001 Jan 1;97(1):46-55. doi: 10.1182/blood.v97.1.46.