Regulation of tumor necrosis factor receptor-1 and the IKK-NF-kappaB pathway by LDL receptor-related protein explains the antiinflammatory activity of this receptor.

Gaultier A, Arandjelovic S, Niessen S, Overton CD, Linton MF, Fazio S, Campana WM, Cravatt BF, Gonias SL
Blood. 2008 111 (11): 5316-25

PMID: 18369152 · PMCID: PMC2396725 · DOI:10.1182/blood-2007-12-127613

Low-density lipoprotein receptor-related protein (LRP-1) functions in endocytosis and in cell signaling directly (by binding signaling adaptor proteins) or indirectly (by regulating levels of other cell-surface receptors). Because recent studies in rodents suggest that LRP-1 inhibits inflammation, we conducted activity-based protein profiling experiments to discover novel proteases, involved in inflammation, that are regulated by LRP-1. We found that activated complement proteases accumulate at increased levels when LRP-1 is absent. Although LRP-1 functions as an endocytic receptor for C1r and C1s, complement protease mRNA expression was increased in LRP-1-deficient cells, as was expression of inducible nitric oxide synthase (iNOS) and interleukin-6. Regulation of expression of inflammatory mediators was explained by the ability of LRP-1 to suppress basal cell signaling through the I kappaB kinase-nuclear factor-kappaB (NF-kappaB) pathway. LRP-1-deficient macrophages, isolated from mice, demonstrated increased expression of iNOS, C1r, and monocyte chemoattractant protein-1 (MCP-1); MCP-1 expression was inhibited by NF-kappaB antagonism. The mechanism by which LRP-1 inhibits NF-kappaB activity involves down-regulating cell-surface tumor necrosis factor receptor-1 (TNFR1) and thus, inhibition of autocrine TNFR1-initiated cell signaling. TNF-alpha-neutralizing antibody inhibited NF-kappaB activity selectively in LRP-1-deficient cells. We propose that LRP-1 suppresses expression of inflammatory mediators indirectly, by regulating TNFR1-dependent cell signaling through the I kappaB kinase-NF-kappaB pathway.

MeSH Terms (19)

Animals Blotting, Western Cells, Cultured Complement Activation Complement System Proteins Electrophoresis, Polyacrylamide Gel Electrophoretic Mobility Shift Assay Flow Cytometry Gene Expression Gene Expression Regulation I-kappa B Kinase Inflammation LDL-Receptor Related Protein-Associated Protein Mice NF-kappa B Polymerase Chain Reaction Receptors, Tumor Necrosis Factor, Type I RNA, Messenger Signal Transduction

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