Inflammatory responses after endothelin B (ET(B)) receptor activation in human monocytes: New evidence for beneficial anti-inflammatory potency of ET(B)-receptor antagonism.

摘要

Endothelin (ET) stimulates potent ET(A)/ET(B) 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 ET(A) or dual ET(A)/ET(B)-receptor antagonism is superior in PAH. The objective of this study was to further elucidate the pro-inflammatory effects of ET-1 on ET(B) receptors in cultured human monocytes (10(5)/20h) compared with non-specific stimulation with LPS in vitro and to define the antagonizing effects of bosentan, a dual ET(A)/ET(B)-receptor antagonist, on inflammatory mediator production. We further hypothesized that ET(B)-receptor antagonism reduces the requirement of PGE(2) to control inflammatory mediator production. Activation of the monocyte ET(B) subtype by ET (1ng/ml) concentration-dependently stimulated TNF-alpha (744%) >PGE(2) (570%) > IL-1beta (112%) and had no effect on 5-lipoxygenase metabolism. Compared with ET a different profile of IL-1beta >TNF-alpha >PGE(2) was induced by LPS. ET(B)-receptor antagonism attenuated ET- and LPS-responses in monocytes, in particular of TNF-alpha and PGE(2) to a similar extend (40%) that were only demonstrable following LPS at therapeutic plasma concentrations of bosentan and had no effect on IL-1beta. Inhibition of ET(B) receptors in LPS-stimulated monocytes by bosentan was responded with suppression of PGE(2) 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 ET(B)-receptor activation with no further control of ET transcription by PGE(2) required following ET(B) receptor antagonism. Therefore, in states of inflammation increased ET(B)-receptor expression and activation mediated by elevated ET concentrations may be an underestimated mechanism, which warrants the application of combined ET(A)/ET(B)-receptor antagonists.