Endotoxemia Induces IκBβ/NF-κB-Dependent Endothelin-1 Expression in Hepatic Macrophages

The Journal of Immunology : Official Journal of the American Association of Immunologists
Sarah McKennaClyde J Wright

Abstract

Elevated serum concentrations of the vasoactive protein endothelin-1 (ET-1) occur in the setting of systemic inflammatory response syndrome and contribute to distal organ hypoperfusion and pulmonary hypertension. Thus, understanding the cellular source and transcriptional regulation of systemic inflammatory stress-induced ET-1 expression may reveal therapeutic targets. Using a murine model of LPS-induced septic shock, we demonstrate that the hepatic macrophage is the primary source of elevated circulating ET-1, rather than the endothelium as previously proposed. Using pharmacologic inhibitors, ET-1 promoter luciferase assays, and by silencing and overexpressing NF-κB inhibitory protein IκB expression, we demonstrate that LPS-induced ET-1 expression occurs via an NF-κB-dependent pathway. Finally, the specific role of the cRel/p65 inhibitory protein IκBβ was evaluated. Although cytoplasmic IκBβ inhibits activity of cRel-containing NF-κB dimers, nuclear IκBβ stabilizes NF-κB/DNA binding and enhances gene expression. Using targeted pharmacologic therapies to specifically prevent IκBβ/NF-κB signaling, as well as mice genetically modified to overexpress IκBβ, we show that nuclear IκBβ is both necessary and sufficient to drive LPS-ind...Continue Reading

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Citations

Feb 1, 2017·American Journal of Reproductive Immunology : AJRI·Yukihiro AzumaTasuku Harada
May 5, 2017·Expert Opinion on Investigational Drugs·Jesus EgidoCarmen Gomez-Guerrero
Jun 27, 2017·Laboratory Investigation; a Journal of Technical Methods and Pathology·Hongfang FengJiangping Xu
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Jul 25, 2019·Pediatric Gastroenterology, Hepatology & Nutrition·Olivier GouletCécile Lambe
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Mar 26, 2021·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Andrey ElchaninovTimur Fatkhudinov
Feb 27, 2018·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Shuwei JinGuoqing Gong

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