Inflammatory responses after endothelin B (ETB) receptor activation in human monocytes: new evidence for beneficial anti-inflammatory potency of ETB-receptor antagonism.
Endothelin (ET) stimulates potent ETA/ETB receptors important in the pathogenesis of pulmonary arterial hypertension (PAH) and fibrosis. Though therapy with ET-receptor antagonists is well established uncertainty exists whether selective ETA or dual ETA/ETB-receptor antagonism is superior in PAH. The objective of this study was to further elucidate the pro-inflammatory effects of ET-1 on ETB receptors in cultured human monocytes (10(5)/20 h) compared with non-specific stimulation with LPS in vitro and to define the antagonizing effects of bosentan, a dual ETA/ETB-receptor antagonist, on inflammatory mediator production. We further hypothesized that ETB-receptor antagonism reduces the requirement of PGE2 to control inflammatory mediator production. Activation of the monocyte ETB subtype by ET (1 ng/ml) concentration-dependently stimulated TNF-alpha (744%) >PGE2 (570%) > IL-1 beta (112%) and had no effect on 5-lipoxygenase metabolism. Compared with ET a different profile of IL-1 beta >TNF-alpha >PGE2 was induced by LPS. ETB-receptor antagonism attenuated ET- and LPS-responses in monocytes, in particular of TNF-alpha and PGE2 to a similar extend (40%) that were only demonstrable following LPS at therapeutic plasma concentrations of bosentan and had no effect on IL-1 beta. Inhibition of ETB receptors in LPS-stimulated monocytes by bosentan was responded with suppression of PGE2 and increased production of leukotrienes indicating strong effects in the cyclooxygenase pathway that is known to control cellular ET transcription. These data suggest an important signaling pathway between ET-induced cytokine production following ETB-receptor activation with no further control of ET transcription by PGE2 required following ETB receptor antagonism. Therefore, in states of inflammation increased ETB-receptor expression and activation mediated by elevated ET concentrations may be an underestimated mechanism, which warrants the application of combined ETA/ETB-receptor antagonists.
Juergens
Uwe R
UR
Department of Pneumology, Allergology and Sleep Medicine, Medical Outpatient Clinic, Bonn University Hospital, Wilhelmstrasse 35-37, D-53111, Germany. juergens_uwe@t-online.de <juergens_uwe@t-online.de>
Racké
Kurt
K
Uen
Sakir
S
Haag
Susanne
S
Lamyel
Fathi
F
Stöber
Meinolf
M
Gillissen
Adrian
A
Novak
Natalija
N
Vetter
Hans
H
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology; D016718:Arachidonic Acid / Q000378:metabolism; D000077300:Bosentan; D002460:Cell Line; D002469:Cell Separation; D015232:Dinoprostone / Q000096:biosynthesis; D065131:Endothelin B Receptor Antagonists; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000139:chemically induced* / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D044023:Receptor, Endothelin B / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D065131:Endothelin B Receptor Antagonists; D053583:Interleukin-1beta; D016859:Lipoxygenase Inhibitors; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D016718:Arachidonic Acid; D015232:Dinoprostone; D000077300:Bosentan