PMID- 12213594
OWN - NLM
STAT- MEDLINE
DCOM- 20021017
LR  - 20190623
IS  - 0006-2952 (Print)
IS  - 0006-2952 (Linking)
VI  - 64
IP  - 5-6
DP  - 2002 Sep
TI  - Reduction of tumor necrosis factor-alpha (TNF-alpha) related nuclear 
      factor-kappaB (NF-kappaB) translocation but not inhibitor kappa-B 
      (Ikappa-B)-degradation by Rho protein inhibition in human endothelial cells.
PG  - 971-7
AB  - Degradation of inhibitor kappa-B (Ikappa-B) followed by translocation of nuclear 
      factor-kappaB (NF-kappaB) into the nucleus and activation of gene expression is 
      essential in tumor necrosis factor-alpha (TNF-alpha)-signaling. In order to 
      analyze the role of Rho proteins in TNF-alpha-induced NF-kappaB-activation in 
      human umbilical cord vein endothelial cells (HUVEC) we used Clostridium difficile 
      toxin B-10463 (TcdB-10463) which inactivates RhoA/Rac1/Cdc42 by glucosylation and 
      Clostridium botulinum C3-toxin which inhibits RhoA/B/C by ADP-ribosylation. 
      Exposure of HUVEC to 10 ng/mL TcdB-10463 or 2.5 microg/mL C3-toxin inhibited 
      TNF-alpha (100 ng/mL)-induced expression of a NF-kappaB-dependent reporter gene. 
      Moreover, preincubation of HUVEC with 10 ng/mL TcdB-10463 reduced 
      TNF-alpha-related expression of interleukin-8 (IL-8), TNF-receptor associated 
      factor-2 (TRAF2), and human inhibitor of apoptosis protein 1 (hIAP1)-mRNA. 
      Blocking of Rho reduced NF-kappaB DNA-binding as shown by electrophoretic 
      mobility shift assays. TcdB-10463 and C3-toxin blocked TNF-alpha-related nuclear 
      translocation of NF-kappaB although Ikappa-Balpha/beta was still degraded. In 
      contrast, TcdB-10463 had no effect on IL-1beta-related NF-kappaB-translocation 
      and activation in HUVEC. Neither 1 microM Rho kinase inhibitor Y-27632 nor 
      microfilament depolymerization by 50 ng/mL C. botulinum C2-toxin blocked 
      TNF-alpha-induced degradation of Ikappa-B, nuclear NF-kappaB translocation or 
      expression of a NF-kappaB-dependent reporter gene. Therefore, TNF-alpha-related 
      Ikappa-B-degradation is Rho-independent in HUVEC, whereas a Rho protein-dependent 
      signal is necessary to induce nuclear transport of NF-kappaB in these cells 
      pointing to a novel and unique role of Rho in NF-kappaB-translocation.
FAU - Hippenstiel, Stefan
AU  - Hippenstiel S
AD  - Charite, Department of Internal Medicine, Humboldt-University, Augustenburger 
      Platz 1, 13353 Berlin, Germany. stefan.hippenstiel@charite.de
FAU - Schmeck, Bernd
AU  - Schmeck B
FAU - Seybold, Joachim
AU  - Seybold J
FAU - Krull, Matthias
AU  - Krull M
FAU - Eichel-Streiber, Christoph
AU  - Eichel-Streiber C
FAU - Suttorp, Norbert
AU  - Suttorp N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Biochem Pharmacol
JT  - Biochemical pharmacology
JID - 0101032
RN  - 0 (I-kappa B Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 9007-49-2 (DNA)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
SB  - IM
MH  - Biological Transport
MH  - Cells, Cultured
MH  - DNA/drug effects/metabolism
MH  - Endothelium, Vascular/*metabolism
MH  - Humans
MH  - I-kappa B Proteins/*metabolism
MH  - NF-kappa B/*metabolism
MH  - Tumor Necrosis Factor-alpha/*metabolism
MH  - rhoA GTP-Binding Protein/*antagonists & inhibitors/metabolism
EDAT- 2002/09/06 10:00
MHDA- 2002/10/18 04:00
CRDT- 2002/09/06 10:00
PHST- 2002/09/06 10:00 [pubmed]
PHST- 2002/10/18 04:00 [medline]
PHST- 2002/09/06 10:00 [entrez]
AID - S0006295202011620 [pii]
AID - 10.1016/s0006-2952(02)01162-0 [doi]
PST - ppublish
SO  - Biochem Pharmacol. 2002 Sep;64(5-6):971-7. doi: 10.1016/s0006-2952(02)01162-0.