TY - JOUR
T1 - 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
AU - Gaultier, Alban
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.
PY - 2008/6/1
Y1 - 2008/6/1
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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U2 - 10.1182/blood-2007-12-127613
DO - 10.1182/blood-2007-12-127613
M3 - Article
C2 - 18369152
AN - SCOPUS:45949089484
SN - 0006-4971
VL - 111
SP - 5316
EP - 5325
JO - Blood
JF - Blood
IS - 11
ER -