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

Alban Gaultier, Sanja Arandjelovic, Sherry Niessen, Cheryl D. Overton, MacRae F. Linton, Sergio Fazio, W. Marie Campana, Benjamin F. Cravatt, Steven L. Gonias

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    Abstract

    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-kκB) pathway. LRP-1-deficient macrophages, isolated from mice, demonstrated increased expression of iNOS, C1r, and monocyte chemoat-tractant 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 IkB kinase-NF-ΚB pathway.

    Original languageEnglish (US)
    Pages (from-to)5316-5325
    Number of pages10
    JournalBlood
    Volume111
    Issue number11
    DOIs
    StatePublished - Jun 1 2008

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    ASJC Scopus subject areas

    • Biochemistry
    • Immunology
    • Hematology
    • Cell Biology

    Cite this

    Gaultier, A., Arandjelovic, S., Niessen, S., Overton, C. D., Linton, M. F., Fazio, S., Campana, W. M., Cravatt, B. F., & Gonias, S. L. (2008). 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. Blood, 111(11), 5316-5325. https://doi.org/10.1182/blood-2007-12-127613