Abstract
Background: Hepatic stellate cells (HSCs) play a central role in the pathogenesis of liver fibrosis and portal hypertension. Following chronic injury, HSCs acquire contractile, proinflammatory and profibrogenic properties. The sympathetic nervous system (SNS) is involved in the regulation of hepatic circulation and recent evidence suggests that it also plays a role in hepatic fibrogenesis. However, the biological actions of norepinephrine (NOR), a key effector of SNS, on human HSCs are largely unknown. Aim: To investigate whether NOR induces calcium increase and stimulates growth and secretion of proinflammatory cytokines in cultured human HSCs. Methods and results: HSCs isolated from normal livers were studied in their activated phenotype (passages 2-5). NOR (10-5-10-7M) induced a marked and dose-dependent increase of [Ca2+]i in Fluo-4 loaded HSCs. NOR-induced calcium increased was blocked by prazosin (a-receptor blocker), while propranolol (b-receptor blocker) had no effect. NOR did not stimulate proliferation of human HSCs, as assessed by 3H-thymidine incorporation. Moreover, NOR stimulated the secretion of MCP-1, interleukin-8 and RANTES in a dose-dependent manner, as assessed by ELISA. Prazosin, but not propranolol, blocked cytokine secretion. We finally explored the intracellular pathways stimulated by NOR in HSCs. NOR stimulated NF-kB, as assessed by a NF-kB-dependent luciferase reporter gene assay and p65 nuclear translocation. In addition, NOR increased AP-1 DNA binding, as assessed by EMSA. Conclusions: NOR exerts vasoactive and proinflammatory properties in HSCs through a-adrenergic receptors. These results suggest that the SNS could participate in livers diseases characterized by increased vascular resistance and hepatic inflammation.
Published Version
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