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

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