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

Research output: Contribution to journalArticle

62 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Low Density Lipoprotein Receptor-Related Protein-1
Tumor Necrosis Factor Receptors
Cell signaling
Anti-Inflammatory Agents
Peptide Hydrolases
Nitric Oxide Synthase Type II
Proteins
Complement C1r
Complement C1s
Phosphotransferases
Monocytes
NF-kappa B
LDL Receptors
Macrophages
Cell Surface Receptors
Neutralizing Antibodies
Inflammation
Interleukin-6
Endocytosis
Messenger RNA

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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

In: Blood, Vol. 111, No. 11, 01.06.2008, p. 5316-5325.

Research output: Contribution to journalArticle

Gaultier, A, Arandjelovic, S, Niessen, S, Overton, CD, Linton, MF, Fazio, S, Campana, WM, Cravatt, BF & Gonias, SL 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, vol. 111, no. 11, pp. 5316-5325. https://doi.org/10.1182/blood-2007-12-127613
Gaultier, Alban ; Arandjelovic, Sanja ; Niessen, Sherry ; Overton, Cheryl D. ; Linton, MacRae F. ; Fazio, Sergio ; Campana, W. Marie ; Cravatt, Benjamin F. ; Gonias, Steven L. / 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. In: Blood. 2008 ; Vol. 111, No. 11. pp. 5316-5325.
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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.",
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AU - Arandjelovic, Sanja

AU - Niessen, Sherry

AU - Overton, Cheryl D.

AU - Linton, MacRae F.

AU - Fazio, Sergio

AU - Campana, W. Marie

AU - Cravatt, Benjamin F.

AU - Gonias, Steven L.

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N2 - 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.

AB - 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.

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