Endotoxemia induces IκBβ/NF-κB-dependent endothelin-1 expression in hepatic macrophages

Sarah McKenna, Megan Gossling, Alejandro Bugarini, Elizabeth Hill, Aimee L. Anderson, Raymond C. Rancourt, Natarajan Balasubramaniyan, Karim C. El Kasmi, Clyde J. Wright

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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-induced ET-1 expression. Together, these results mechanistically link the innate immune response mediated by IκBβ/NF-κB to ET-1 expression and potentially reveal therapeutic targets for patients with Gram-negative septic shock.

Original languageEnglish (US)
Pages (from-to)3866-3879
Number of pages14
JournalJournal of Immunology
Volume195
Issue number8
DOIs
StatePublished - Oct 15 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.

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