WITHDRAWN: Selenium supplementation inhibits lipopolysaccharide-induced endometritis by decreasing the cholesterol content of lipid rafts

Abstract

We investigated the protective effects of selenium (Se) against lipopolysaccharide (LPS)-induced endometritis in mice. Female mice were fed Se-containing diets prior to being challenged with an intrauterine injection of LPS. Histopathological changes, expression of Toll-like receptor 4 (TLR4)-related signaling molecules and inflammatory cytokines, as well as tissue and lipid raft-associated cholesterol levels were measured in ex-vivo and in vitro experiments conducted with uterine tissues and cells. Results showed that Se reversed LPS-induced changes in uterine histopathology and decreased myeloperoxidase activity as well as levels of the pro-inflammatory cytokines TNF-α and IL-1β in excised uteri. Se supplementation also hampered LPS-induced TLR4 signaling by attenuating NF-κB and IRF3 expression, and promoted the degradation of cholesterol in both uterine tissues and lipid rafts from cultured endometrial cells. In these cells, Se also inhibited LPS-induced production of inflammatory cytokines, including TNF-α, IL-1β, and IL-6, and blocked expression of NF-κB and IRF3. These protective effects of Se were abolished by knocking down the cholesterol-sensing liver x receptor alpha (LxRα), which resulted in downregulation of the cholesterol efflux regulatory protein ABCA1. We conclude that the anti-inflammatory actions of Se against LPS-induced endometritis are associated with upregulation of the LxRα-ABCA1 pathway, leading to lipid raft destruction through cholesterol-depletion, which impedes the translocation of TLR4 to lipid rafts and blocks the ensuing inflammatory cascade.