Regulation of cytokine expression by Schwann cells in response to α 2 ‐macroglobulin binding to LRP1

Abstract Binding of activated α 2 ‐macroglobulin (α 2 M) to LDL receptor‐related protein‐1 (LRP1) in Schwann cells activates ERK/MAP kinase and Akt and thereby promotes cell survival and migration. The goal of this study was to determine whether α 2 M binding to LRP1 regulates expression of cytokines and chemokines. To assess the LRP1 response selectively, we studied primary cultures of rat Schwann cells. In a screening assay that detects 84 gene products, monocyte chemoattractant protein‐1 (MCP‐1/CCL2) mRNA expression was increased more than 13‐fold in Schwann cells treated with activated α 2 M. The effects of α 2 M on MCP‐1 expression were selective, because expression of the general proinflammatory cytokine tumor necrosis factor‐α (TNF‐α) was not induced. We confirmed that α 2 M selectively induces expression of MCP‐1 and not TNF‐α in single‐target qPCR assays. MCP‐1 protein accumulated at increased levels in conditioned medium of α 2 M‐treated cells. LRP1 was necessary for induction of MCP‐1 expression, as determined in experiments with the LRP1 antagonist receptor‐associated protein, a mutated form of full‐length α 2 M that does not bind LRP1, and in studies with Schwann cells in which LRP1 was silenced. Inhibiting ERK/MAP kinase activation blocked expression of MCP‐1. These studies support a model in which LRP1 regulates multiple aspects of Schwann cell physiology in the response to PNS injury. © 2011 Wiley‐Liss, Inc.