Help Privacy Policy Disclaimer
  Advanced SearchBrowse


  Proteasome inhibition leads to NF-kappaB-independent IL-8 transactivation in human endothelial cells through induction of AP-1

Hipp, M. S., Urbich, C., Mayer, P., Wischhusen, J., Weller, M., Kracht, M., et al. (2002). Proteasome inhibition leads to NF-kappaB-independent IL-8 transactivation in human endothelial cells through induction of AP-1. Eur J Immunol, 32(8), 2208-17. doi:10.1002/1521-4141(200208)32:8<2208:AID-IMMU2208>3.0.CO;2-2.

Item is


show Files




Hipp, M. S.1, Author           
Urbich, C.2, Author
Mayer, P.3, Author           
Wischhusen, J.2, Author
Weller, M.4, Author           
Kracht, M.2, Author
Spyridopoulos, I.2, Author
1Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              
2External Organizations, ou_persistent22              
3Division Prof. Dr. Joachim H. Ullrich, MPI for Nuclear Physics, Max Planck Society, ou_904547              
4Former Dept. Micro/Nanomechanics of Thin Films and Biological Systems, Max Planck Institute for Intelligent Systems, Max Planck Society, ou_1497655              


Free keywords: Cells, Cultured Cysteine Endopeptidases/physiology Endothelium, Vascular/cytology/*metabolism Humans Interleukin-8/*genetics/secretion Multienzyme Complexes/*antagonists & inhibitors/physiology NF-kappa B/*physiology Proteasome Endopeptidase Complex Transcription Factor AP-1/*biosynthesis *Transcriptional Activation Tumor Suppressor Protein p53/physiology
 Abstract: IL-8 is an important mediator of leukocyte trafficking and activation, participating in tumor angiogenesis, inflammatory processes and coronary atherosclerosis. Under flow conditions IL-8, in conjunction with MCP-1, triggers the firm adhesion of monocytes to the vascular endothelium. While previous studies have suggested the requirement of NF-kappaB for IL-8 secretion by endothelial cells, we investigated the possibility of IL-8 transactivation under conditions of NF-kappaB suppression. Inhibition of the proteasome by MG-132 or lactacystin completely blocked TNF-alpha-induced IkappaBalpha degradation as well as NF-kappaB activity in human arterial endothelial cells. Surprisingly, basal secretion of IL-8 protein was eight- to tenfold induced by proteasome inhibitors, while MCP-1 expression was, as expected, completely down-regulated. IL-8 was up-regulated at the transcriptional level, and promoter studies proved a more than ninefold induction of transcription factor AP-1 activity to be the cause of increased IL-8 transcription. Mutation of the AP-1 binding site in an IL-8 promoter construct completely abrogated this effect, while mutation of the NF-kappaB motif did not influence IL-8 transactivation by proteasome inhibitors. With DNA binding assays we found a seven- to eightfold induction of phosphorylated c-Jun and hence JNK kinase activity under MG-132 treatment. Induction of JNK kinase appeared independent of the cell type, even in tumor cell lines not responding to proteasome inhibitors. Since neither inactivation of p53 in wild-type p53 cells nor reintroduction of functional p53 into p53(-/-) cells affected MG-132-inducible IL-8 secretion, a direct influence of p53 on IL-8 regulation could be excluded. These results show that proteasome inhibitors can not only lead to functional AP-1 induction by enhanced c-Jun phosphorylation, but also transactivate the IL-8 gene in human endothelial cells despite complete suppression of NF-kappaB activity.


 Dates: 2002
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: Other: 12209633
DOI: 10.1002/1521-4141(200208)32:8<2208::AID-IMMU2208>3.0.CO;2-2
ISSN: 0014-2980 (Print) 0014-2980 (Linking)
URI: http://www.ncbi.nlm.nih.gov/pubmed/12209633
 Degree: -



Legal Case


Project information


Source 1

Title: Eur J Immunol
Source Genre: Journal
Publ. Info: -
Pages: - Volume / Issue: 32 (8) Sequence Number: - Start / End Page: 2208 - 17 Identifier: -