Activated α2-macroglobulin induces cell proliferation and mitogen-activated protein kinase activation by LRP-1 in the J774 macrophage-derived cell line

The low-density lipoprotein receptor-related protein-1 (LRP-1) is an endocytic receptor of activated forms of the proteinase inhibitor alpha 2-macroglobulin (alpha M-2*). It has been proposed that alpha M-2* and LRP-1 modulate diverse cellular processes, including cell adhesion, proliferation, and migration, which are involved in inflammation and tumor progression. However, relatively little is known about the role of alpha M-2*/LRP-1 interaction on these processes. In this work, we demonstrate that alpha M-2* binding to LRP-1 induces cell proliferation and MAPK activation in the J774 macrophage-derived cell line, which were blocked by RAP, an antagonist of LRP-1-binding ligands, and by PD980059, a specific inhibitor for the Mek1-ERK1/2 pathway. In addition, we demonstrate that LPS, a bacterial product that it is known to down-regulate the LRP-1 expression on macrophage, abrogated the signaling activity triggered by alpha M-2* on LPS-treated J774 cells. These results suggest that alpha M-2*/LRP-1 interaction constitutes a key role in the macrophage functioning during inflammation and cancer. (c) 2007 Elsevier Inc. All rights reserved.