LXRα represses LPS-induced inflammatory responses by competing with IRF3 for GRIP1 in Kupffer cells

•LPS-induced TNF-, IFN- and IL-1 < beta > generation was reduced by pretreatment with LXR < alpha > agonist.•The LPS-TLR4 signalling pathway involves IRF3 and GRIP1 co-activation of NF-kB.•LXR < alpha > agonist, T0901317, has little effect on the expression of either IRF3 or GRIP1.•Agonist-activated LXR < alpha > competes with IRF3 for GRIP1 and this is the mechanism by which TLR4 signalling is inhibited.

Liver X receptors (LXRs) in the nucleus play important roles in lipid metabolism and inflammation. The mechanism of LXR regulation of the LPS-induced Toll-like receptor 4 (TLR4) inflammatory signaling pathway remains to be elucidated. C57/BL6 mice were randomly divided into four groups: control, T0901317 (a LXRs agonist), LPS and T0901317 + LPS. Additionally, Kupffer cells isolated from male C57/BL6 mice were divided into the same four groups. A decreased amount of inflammatory cells infiltrated the portal areas and the hepatic sinusoids in the livers of mice in the T0901317 + LPS group than in those of mice in the LPS group. In the T0901317 + LPS group, the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor alpha (TNF-α) were lower, while the serum level of interleukin-10 (IL-10) was higher. In vitro, Kupffer cells pretreated with T0901317 for 24 h presented reduced TNF-α, interferon-beta (IFN-β) and interleukin-1 beta (IL-1β) levels, while the IL-10 level increased; however, the mRNA and protein expression levels of interferon regulatory factor 3 (IRF3) and glucocorticoid receptor-interacting protein 1 (GRIP1) were not significantly reduced. The co-IP data illustrated that LXRα bound to GRIP1 specifically in the T0901317 + LPS group, while less IRF3 was bound to GRIP1 in the T0901317 + LPS group than in the LPS group. Furthermore, the DNA-binding activity of NF-κB was decreased by pretreating Kupffer cells with T0901317 for 24 h. These results suggest that activated LXRα competes with IRF3 for GRIP1 binding, thus repressing IRF3 and NF-κB transcriptional activity and inhibiting the inflammatory response initiated by LPS in Kupffer cells.