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ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway.

Abstract：

:Systemic inflammatory response syndrome (SIRS) is associated with excessive inflammatory response, however, the pathophysiology of inflammation is poorly understood. The retinoid-related orphan receptor α (RORα) is a key inflammatory regulator, but the mechanisms underlying its role remain unclear. The aim of this study was to investigate how RORα was involved in the regulation of inflammatory response. Here we put forward a hypothesis that RORα might negatively regulate inflammatory response by controlling silent information regulator Sirtuin 1 (SIRT1) expression. Stimulation of macrophages in vitro with LPS and LPS administration in vivo were used to explore the function of RORα and the relationship between RORα and SIRT1. We found that the level of RORα was suppressed in macrophages stimulated with LPS and overexpression or knockdown of RORα by transfection with lentivirus or siRNAs significantly decreased or increased, respectively, the pro-inflammatory cytokines IL-1β, TNF, IL-6 and MCP-1. Importantly, overexpression of RORα suppressed inflammation and alleviated LPS-induced organ injury in vivo. Further study showed that RORα could regulate SIRT1 expression and, consequently, affect deacetyation and nuclear translocation of nuclear factor-kappa B (NF-κB) subunit p65. Moreover, the activation of SIRT1 by its specific agonist, SR1720, could reduce the expression of proinflammatory cytokines in RORα knockdown macrophages stimulated with LPS. In conclusion, we demonstrated that RORα could alleviate LPS-induced inflammation and organ injury both in vivo and in vitro by blocking NF-κB p65 nuclear translocation and restricting acetylation of NF-κB p65 at lysine 310 via the regulation of SIRT1 expression. Targeting RORα might be a promising therapeutic strategy to regulate inflammatory disorders.

journal_name

Arch Biochem Biophys

journal_title

Archives of biochemistry and biophysics

authors

Han S,Li Z,Han F,Jia Y,Qi L,Wu G,Cai W,Xu Y,Li C,Zhang W,Hu D

doi

10.1016/j.abb.2019.05.003

subject

Has Abstract

pub_date

2019-06-15 00:00:00

pages

1-8

eissn

0003-9861

issn

1096-0384

pii

S0003-9861(19)30130-4

journal_volume

668

pub_type

杂志文章

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ROR alpha protects against LPS-induced inflammation by down-regulating SIRT1/NF-kappa B pathway.