Role of NF-kappaB pathway and potential of estrogen and its nanoformulation in sepsis.

摘要

Sepsis is a common healthcare problem in the United States. Data have shown that women are affected with a lower incidence and fewer complications than men. This gender dimorphism has been attributed to estrogen. It has been shown that estrogen has many immunomodulatory functions, affecting many cytokines/chemokines. Our study focuses on whether the effects of estrogen in sepsis are genomic or non-genomic. HAEC cells were grown and treated with estradiol (works on nuclear and cytoplasmic receptors) and estradiol conjugated with nanoparticles (estradiol-NP, works exclusively on cytoplasmic receptors). Both formulations were tagged with Alexa Fluor®488 dye, and confocal images of the cells were taken. Sepsis was induced in C57BL/6NHsd mice using the CLP model and in BALB/C-Tg (NF κB-RE-luc)-Xen mice using LPS. Effects of estradiol and estradiol-NP on IL-1, IL-6, IL-10, IL-17, TNF-α, and IFN-γ were evaluated by the multiplex cytokines assay. Effects on NF-κB were evaluated by IVIS Imaging and NF-κB Luciferase Reporter HeLa Stable Cell line. Confocal images confirmed that estradiol-NPs do not gain access to the nucleus. Estradiol and estradiol-NP significantly enhanced the production of IL-10, and estradiol-NP significantly enhanced production of IFN-γ. Estradiol suppresses NF-κB and enhances the production of IL-10 and IFN-γ likely via non-genomic pathways. Different doses given intravenously might be required to see effects on other cytokines and survival after CLP.