Endothelin-1 induces CD40 but not IL-6 in human monocytes via the proinflammatory transcription factor NF-kappaB.
The vasoactive peptide endothelin-1 (ET-1) may contribute to the pathogenesis of atherosclerosis and its acute complications. Because inflammation of the vessel wall is a characteristic feature of atherosclerosis, this study investigated the effect of ET-1 on the proinflammatory transcription factor NF-kappaB in monocytes. Monocyte/macrophages are a major source of inflammatory mediators in atheroma and are located in rupture prone plaque areas. In human monocytes ET-1 caused NF-kappaB activation. Specificity of ET-1-induced NF-kappaB activation was ascertained by supershift and competition experiments. This ET-1 effect was blocked by the ET-A-receptor antagonist BQ-123 but not by the ET-B-receptor antagonist BQ-788. PI-1, a specific inhibitor of the IkappaB-alpha-degrading proteasome complex, also prevented NF-kappaB activation. ET-1 stimulated expression of the proinflammatory molecule CD40 but not of the cytokine IL-6 in a NF-kappaB-dependent manner.


CONCLUSIONS
The data demonstrate the ability of ET-1 to activate inflammatory pathways in human monocytes differentially.
Browatzki
M
M
Department of Cardiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Pfeiffer
C A H
CA
Schmidt
J
J
Kranzhöfer
R
R
D000959:Antihypertensive Agents / Q000494:pharmacology; D019013:CD40 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D014657:Vasculitis / Q000276:immunology / Q000378:metabolism
D000959:Antihypertensive Agents; D019013:CD40 Antigens; D019332:Endothelin-1; D015850:Interleukin-6; D016328:NF-kappa B; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; C086539:BQ 788; C072247:cyclo(Trp-Asp-Pro-Val-Leu)