IL-1beta-induced monocyte chemoattractant protein-1 gene expression in endothelial cells is blocked by proteasome inhibitors.
Human monocyte chemoattractant protein-1 (MCP-1) is expressed by a variety of cell types in response to various stimuli. MCP-1 expressed by the endothelium plays an important role in cell migration and activation. MCP-1 is a major chemoattractant for monocytes, T lymphocytes, and basophils. In the present study, we present evidence that the proteasome complex is involved in mediating the interleukin (IL)-1beta induction of MCP-1 in endothelial cells. We present evidence that a proteasome inhibitor, N-acetyl-leucinyl-leucinyl-norleucinal (norLeu), and the protease inhibitor tosyl-Phe-chloromethylketone (TPCK) block IL-1beta induction of MCP-1 protein expression. norLeu and TPCK also blocked IL-1beta-induced MCP-1 promoter-driven reporter gene expression as well as nuclear factor (NF)-kappaB-mediated reporter gene expression. The effects of norLeu were due to its inhibition of the proteasome rather than calpain, because other calpain inhibitors had no effect on MCP-1 expression. In contrast to TPCK, which blocked NF-kappaB translocation to the nucleus, norLeu had no effect on NF-kappaB nuclear translocation or IL-1beta-induced phosphorylation of p65. This study demonstrates that the proteasome pathway is involved in IL-1beta-induced MCP-1 gene expression in human endothelial cells.
Parry
G C
GC
Department of Immunology, The Scripps Research Institute, La Jolla, Calif, USA.
Martin
T
T
Felts
K A
KA
Cobb
R R
RR
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology*; D007976:Leupeptins / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014108:Tosylphenylalanyl Chloromethyl Ketone / Q000494:pharmacology
D018932:Chemokine CCL2; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D007976:Leupeptins; D009097:Multienzyme Complexes; D016328:NF-kappa B; D015842:Serine Proteinase Inhibitors; C063261:acetylleucyl-leucyl-norleucinal; D014108:Tosylphenylalanyl Chloromethyl Ketone; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex