Molecular mechanism underlying lipopolysaccharide-mediated expression of LCN2 in mesangial cells (136.9)

Abstract

Abstract The neutrophil gelatinase-associated lipocalin 2 (LCN2) is a critical inflammatory mediator highly expressed in both acute and chronic inflammatory conditions. In particular, LCN2 produced in kidney mesangial cells contributes to tubular damage and kidney failure. In this report, we demonstrated that the interleukin 1 receptor associated kinase 1 (IRAK-1) is essential for lipopolysaccharide (LPS)-induced expression of LCN2 in kidney mesangial cells in vtro and kidney tissues in vivo. Mechanistically, we demonstrated that C/EBPδ is critically involved in the expression of LCN2. Through chromatin immunoprecipitation assays, we showed that LPS recruits C/EBPδ to the LCN2 promoter from WT, but not IRAK-1-/- cells. Furthermore, we revealed that both de novo synthesis and activation of C/EBPδ mediated by IRAK-1 are required for LCN2 expression. Blockage of new protein synthesis using cyclohexamide significantly reduces C/EBPδ and LCN2 expression in WT, but not IRAK-1-/- cells. The expression of C/EBPδ and LCN2 can also be effectively blocked by an IKKϵ inhibitor in WT, but not IRAK-1-/- cells, suggesting the IRAK-1 contributes to C/EBPδ expression though an IKKϵ-dependent mechanism. Taken together, this study has identified an integrated intracellular network involved in LPS-induced expression of LCN2. In addition, this research provides evidence that IRAK-1 is an important target with therapeutic potential in treating acute and chronic inflammatory diseases.