Endothelin-1 induces interleukin-6 release via activation of the transcription factor NF-kappaB in human vascular smooth muscle cells.
The potent vasoconstrictor peptide endothelin-1 (ET-1) has been implicated in the pathophysiology of atherosclerosis and its complications. Since inflammation of the vessel wall is a hallmark of atherosclerosis, the purpose of the present study was to investigate the influence of ET-1 on cytokine production in human vascular smooth muscle cells (SMC) as a marker of inflammatory cell activation. ET-1 (100 pM - 1 microM) stimulated interleukin-6 (IL-6) secretion from human vascular SMC in a concentration-dependent manner. The ET-A-receptor antagonist BQ-123 (10 microM), but not the ET-B-receptor antagonist BQ-788, inhibited IL-6 release. ET-1 also transiently increased IL-6 mRNA compatible with regulation of IL-6 release at the pretranslational level. Electrophoretic mobility shift assays demonstrated time- and concentration-dependent activation of the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) in ET-1-stimulated human vascular SMC. A decoy oligodeoxynucleotide bearing the NF-kappaB binding site inhibited ET-1-stimulated IL-6 release to a great extent suggesting that this transcription factor plays a key role for cytokine production elicited by ET-1. Moreover, the antioxidant pyrrolidine dithiocarbamate (10 microM) inhibited ET-1-induced IL-6 release indicating involvement of reactive oxygen species in ET-1 signaling. ET-1-stimulated IL-6 secretion was also suppressed by diphenylene iodonium (40 microM), an inhibitor of flavon-containing enzymes such as NADH/NADPH oxidase. The results demonstrate the ability of ET-1 to induce an inflammatory response in human vascular SMC. These observations may contribute to a better understanding of the role of ET-1 in inflammatory activation of the vessel wall during atherogenesis.
Browatzki
M
M
Medizinische Universitätsklinik, Abt. Kardiologie, Heidelberg, Germany.
Schmidt
J
J
Kübler
W
W
Kranzhöfer
R
R
D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016328:NF-kappa B / Q000502:physiology*; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000502:physiology
D000975:Antioxidants; D019332:Endothelin-1; D015850:Interleukin-6; D016328:NF-kappa B; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin