The Liver X Receptor Is Upregulated in Monocyte-Derived Macrophages and Modulates Inflammatory Cytokines Based on LXRalpha Polymorphism

Abstract

Liver X receptors (LXRs) have emerged as important regulators of inflammatory gene expression. Previously, we had reported that an LXRalpha gene promoter polymorphism (-1830 T > C) is associated with systemic lupus erythematosus (SLE). Therefore, we assessed cytokine expression in relation to LXRalpha polymorphism in monocyte-derived macrophages from patients with SLE. Macrophages were obtained after 72 hours of culture of human monocytes supplemented with phorbol 12-myristate 13-acetate. Cells were transfected with LXRalpha promoter constructs. Additionally, peripheral blood mononuclear cell- (PBMC-) derived macrophages from the patients were evaluated for proinflammatory cytokines in relation to the genotypes of LXRalpha -1830 T > C. The expression of LXRalpha was increased in macrophages: levels of proinflammatory cytokines were decreased with LXRalpha expression. Production of proinflammatory cytokines varied depending on LXRalpha -1830 T > C genotype. In particular, expression of LXRalpha was decreased and that of proinflammatory cytokines was increased for LXRalpha -1830 TC genotype compared to that for TT genotype. The data were consistent in PBMC-derived macrophages from patients with SLE. Increased proinflammatory cytokines is related to TLR7 and TLR9 expression. These data suggest that the expression levels of LXRalpha, according to LXRalpha -1830 T > C genotype, may contribute to the inflammatory response by induction of inflammatory cytokines in SLE.