NRF2 Exerts Anti-Inflammatory Effects in LPS-Induced gEECs by Inhibiting the Activation of the NF-κB

Nuclear factor E2-related factor 2 (NRF2) plays an anti-inflammatory role in several pathological processes, but its function in lipopolysaccharide- (LPS-) induced goat endometrial epithelial cells (gEECs) is still unknown. We designed a study to investigate the function of NRF2 in LPS-induced gEECs. LPS was found to increase the NRF2 expression and the nuclear abundance of NRF2 in gEECs in a dose-dependent manner. NRF2 knockout (KO) not only increased the expression of LPS-induced proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6 and IL-8) but also increased the expression of TLR4, p-I kappa B alpha/I kappa B alpha, and p-p65/p65 proteins. Immunoprecipitation experiments showed that NRF2 directly binds to p65 in the nucleus and inhibits the binding of p65 to downstream target genes (TNF-alpha, IL-1 beta, IL-6, and IL-8). Even though a NF-kappa B/p65 inhibitor (PDTC) reduced the LPS-induced NRF2 expression and nuclear abundance of NRF2, overexpressing TNF-alpha reversed the inhibitory effects of PDTC on the NRF2 expression and on its abundance in the nucleus. Similarly, knockdown of the proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6, or IL-8) significantly decreased the LPS-induced NRF2 expression and NRF2 in the nucleus. In conclusion, our data suggest that proinflammatory cytokines induced by LPS through the TLR4/NF-kappa B pathway promote the NRF2 expression and its translocation into the nucleus. Our work also suggests that NRF2 inhibits the expression of proinflammatory cytokines by directly binding to p65.

Automated summary

The study found that proinflammatory cytokines induced by LPS through the TLR4/NF-kappa B pathway promote the expression of NRF2 and its translocation into the nucleus. Additionally, NRF2 inhibits the expression of proinflammatory cytokines by directly binding to p65.