Regulation of cytokine expression by Schwann cells in response to α2-macroglobulin binding to LRP1

✍ Scribed by Yang Shi; Tomonori Yamauchi; Alban Gaultier; Shinako Takimoto; W. Marie Campana; Steven L. Gonias

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 465 KB
• Volume: 89
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.22576

✦ Synopsis

Binding of activated a 2 -macroglobulin (a 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 a 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 a 2 M. The effects of a 2 M on MCP-1 expression were selective, because expression of the general proinflammatory cytokine tumor necrosis factor-a (TNF-a) was not induced. We confirmed that a 2 M selectively induces expression of MCP-1 and not TNF-a in single-target qPCR assays. MCP-1 protein accumulated at increased levels in conditioned medium of a 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 fulllength a 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. V