Regulation of macrophage α2-macroglobulin receptor/low density lipoprotein receptor-related protein by lipopolysaccharide and interferon-γ

Abstract

α2-Macroglobulin receptor/low density lipoprotein receptor-related protein (α2M-R/LRP) is a broad specificity receptor that may function in lipoprotein metabolism, proteinase regulation, and growth factor regulation. In this study, we demonstrated that α2M-R/LRP expression in macrophages can be markedly decreased by LPS and by IFN-γ. Regulation of α2M-R/LRP in RAW 264.7 cells was demonstrated at the mRNA, antigen, and receptor-function levels. In receptor-function studies, the decrease in α2M-R/LRP expression was detected as a 90% decrease in the Bmax or maximum receptor binding capacity for activated α2M after treatment with LPS or IFN-γ. Western blot analysis of whole cell lysates demonstrated significant loss of α2M-R/LRP heavy-chain. Northern blot analysis of poly(A)+ RNA revealed a marked decrease in α2M-R/LRP mRNA after treatment with LPS (79% decrease) or IFN-γ (70% decrease). Other cytokines, including tumor necrosis factor-α, transforming growth factor-β1, and interleukin-6 did not regulate α2M-R/LRP. The ability of LPS and IFN-γ to regulate α2M-R/LRP was confirmed in experiments with primary cultures of murine bone marrow macrophages. These studies demonstrate that macrophage α2M-R/LRP is subject to significant downregulation by physiologically significant cytokines and signaling macromolecules.