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.
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.
Gaultier
Alban
A
Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA 92093-0612, USA.
Arandjelovic
Sanja
S
Niessen
Sherry
S
Overton
Cheryl D
CD
Linton
MacRae F
MF
Fazio
Sergio
S
Campana
W Marie
WM
Cravatt
Benjamin F
BF
Gonias
Steven L
SL
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003167:Complement Activation / Q000502:physiology*; D003165:Complement System Proteins; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015870:Gene Expression; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D026563:LDL-Receptor Related Protein-Associated Protein / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D026563:LDL-Receptor Related Protein-Associated Protein; D016328:NF-kappa B; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D003165:Complement System Proteins; D051550:I-kappa B Kinase