Regulation of tumor necrosis factor receptor-1 and the IKK-NF-κB pathway by LDL receptor–related protein explains the antiinflammatory activity of this receptor
| Autor: | Steven L. Gonias, Alban Gaultier, Benjamin F. Cravatt, Sherry Niessen, Sanja Arandjelovic, Sergio Fazio, MacRae F. Linton, Cheryl D. Overton, W. Marie Campana |
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| Rok vydání: | 2008 |
| Předmět: |
Cell signaling
Blotting Western Immunology Gene Expression Electrophoretic Mobility Shift Assay IκB kinase Biology Polymerase Chain Reaction Hemostasis Thrombosis and Vascular Biology Biochemistry Mice Animals RNA Messenger LDL-Receptor Related Protein-Associated Protein Autocrine signalling Receptor Complement Activation Cells Cultured Inflammation NF-kappa B Complement System Proteins Cell Biology Hematology Flow Cytometry Molecular biology I-kappa B Kinase Cell biology Gene Expression Regulation Receptors Tumor Necrosis Factor Type I LDL receptor Electrophoresis Polyacrylamide Gel lipids (amino acids peptides and proteins) Tumor necrosis factor alpha Tumor necrosis factor receptor 1 Signal transduction Signal Transduction |
| Zdroj: | Blood. 111:5316-5325 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | 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 IκB kinase–nuclear factor-κB (NF-κB) 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-κB antagonism. The mechanism by which LRP-1 inhibits NF-κB activity involves down-regulating cell-surface tumor necrosis factor receptor-1 (TNFR1) and thus, inhibition of autocrine TNFR1-initiated cell signaling. TNF-α–neutralizing antibody inhibited NF-κB 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 IκB kinase–NF-κB pathway. |
| Databáze: | OpenAIRE |
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