PMID- 12237332
OWN - NLM
STAT- MEDLINE
DCOM- 20021011
LR  - 20190607
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 62
IP  - 4
DP  - 2002 Oct
TI  - Tranilast inhibits cytokine-induced nuclear factor kappaB activation in vascular 
      endothelial cells.
PG  - 856-63
AB  - Tranilast [N-(3,4-dimethoxycinnamoyl)anthranilic acid] inhibits vascular 
      inflammation. However, the relevant anti-inflammatory mechanisms are not 
      completely understood. We studied the effects of tranilast on nuclear 
      factor-kappaB (NF-kappaB)-dependent endothelial cell adhesion molecule expression 
      and transcriptional regulation. Cultured human umbilical vein endothelial cells 
      were preincubated with 12.5 to 100 microg/ml tranilast. Tumor necrosis 
      factor-alpha (TNF-alpha)-induced endothelial VCAM-1, ICAM-1, and E-selectin 
      surface expression was inhibited dose dependently. Maximal inhibition achieved 
      with 100 microg/ml tranilast was 38 +/- 6.9, 31.8 +/- 1.5, and 31.9 +/- 1.9%, 
      respectively (mean +/- S.E.M., p < 0.001, n = 5). Secretion of interleukin 6, 
      which is also NF-kappaB-sensitive, was significantly inhibited by tranilast. 
      Endothelial MHC-I expression, which is independent of NF-kappaB, was not 
      inhibited. Although cytokine-induced degradation of NF-kappaB inhibitor proteins 
      (IkappaB-alpha, -beta, and -epsilon), nuclear translocation of NF-kappaB, and 
      binding of NF-kappaB to kappaB cis-acting elements in the adhesion molecule 
      promoters were not affected by tranilast, ICAM-1-kappaB and E-selectin-kappaB 
      reporter gene activity was inhibited by 53% (n = 5, p < 0.01) and 51% (n = 5, p < 
      0.001), respectively. In contrast, using SP-1 and C/EBP constructs, reporter gene 
      activity was not altered. Expression of the transcriptional coactivator cAMP 
      response element binding protein binding protein (CBP) was inhibited by 
      tranilast, resulting in a loss of interaction between NF-kappaB and CBP. 
      Therefore, in therapeutically relevant concentrations (50 microg/ml), tranilast 
      inhibits NF-kappaB-dependent transcriptional activation by interfering with the 
      NF-kappaB/CBP association. We propose that inhibition of NF-kappaB dependent gene 
      transcription contributes to the anti-inflammatory effects of tranilast.
FAU - Spiecker, Martin
AU  - Spiecker M
AD  - Department of Medicine II, University of Bochum, Bochum, Germany. 
      martin.spieker@ruhr.uni-bochum.de
FAU - Lorenz, Ioana
AU  - Lorenz I
FAU - Marx, Nikolaus
AU  - Marx N
FAU - Darius, Harald
AU  - Darius H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Activating Transcription Factor 1)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Cytokines)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (ortho-Aminobenzoates)
RN  - 9007-49-2 (DNA)
RN  - EC 6.- (Ligases)
RN  - EC 6.- (guanosine 3',5'-polyphosphate synthetases)
RN  - HVF50SMY6E (tranilast)
SB  - IM
MH  - Activating Transcription Factor 1
MH  - Active Transport, Cell Nucleus/drug effects
MH  - Cell Adhesion Molecules/metabolism
MH  - Cells, Cultured
MH  - Cytokines/*pharmacology
MH  - DNA/drug effects/metabolism
MH  - *DNA-Binding Proteins
MH  - Dimerization
MH  - Endothelium, Vascular/*drug effects/metabolism
MH  - Humans
MH  - I-kappa B Proteins/metabolism
MH  - Ligases/metabolism
MH  - NF-kappa B/genetics/*metabolism
MH  - Transcription Factors/drug effects/metabolism
MH  - Transcription, Genetic/drug effects
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - ortho-Aminobenzoates/*pharmacology
EDAT- 2002/09/19 10:00
MHDA- 2002/10/12 04:00
CRDT- 2002/09/19 10:00
PHST- 2002/09/19 10:00 [pubmed]
PHST- 2002/10/12 04:00 [medline]
PHST- 2002/09/19 10:00 [entrez]
AID - 10.1124/mol.62.4.856 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2002 Oct;62(4):856-63. doi: 10.1124/mol.62.4.856.