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Blood, 1 June 2008, Vol. 111, No. 11, pp. 5316-5325. Prepublished online as a Blood First Edition Paper on March 27, 2008; DOI 10.1182/blood-2007-12-127613. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-12-127613v1 111/11/5316    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Gaultier, A. Articles by Gonias, S. L. Search for Related Content PubMed PubMed Citation Articles by Gaultier, A. Articles by Gonias, S. L. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Regulation of tumor necrosis factor receptor-1 and the IKK-NF-B pathway by LDL receptor–related protein explains the antiinflammatory activity of this receptor Alban Gaultier1,*, Sanja Arandjelovic1,*, Sherry Niessen2, Cheryl D. Overton3, MacRae F. Linton3, Sergio Fazio3, W. Marie Campana4, Benjamin F. Cravatt, III2, and Steven L. Gonias1 1 Department of Pathology, University of California San Diego School of Medicine, La Jolla; 2 Department of Chemical Biology and the Skaggs Institute for Chemical Biology, Scripps Research institute, La Jolla, CA; 3 Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN; and 4 Department of Anesthesiology, University of California San Diego School of Medicine, La Jolla 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 IB kinase–nuclear factor-B (NF-B) 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-B antagonism. The mechanism by which LRP-1 inhibits NF-B activity involves down-regulating cell-surface tumor necrosis factor receptor-1 (TNFR1) and thus, inhibition of autocrine TNFR1-initiated cell signaling. TNF-–neutralizing antibody inhibited NF-B 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 IB kinase–NF-B pathway. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Suzuki, N. Nagai, K. Yamakawa, J. Kawakami, H. R. Lijnen, and K. Umemura Tissue-type plasminogen activator (t-PA) induces stromelysin-1 (MMP-3) in endothelial cells through activation of lipoprotein receptor-related protein Blood, October 8, 2009; 114(15): 3352 - 3358. [Abstract] [Full Text] [PDF] P. L.S.M. Gordts, S. Reekmans, A. Lauwers, A. Van Dongen, L. Verbeek, and A. J.M. Roebroek Inactivation of the LRP1 Intracellular NPxYxxL Motif in LDLR-Deficient Mice Enhances Postprandial Dyslipidemia and Atherosclerosis Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1258 - 1264. [Abstract] [Full Text] [PDF] Y. Shi, E. Mantuano, G. Inoue, W. M. Campana, and S. L. Gonias Ligand Binding to LRP1 Transactivates Trk Receptors by a Src Family Kinase-Dependent Pathway Sci. Signal., April 28, 2009; 2(68): ra18 - ra18. [Abstract] [Full Text] [PDF] A. Gaultier, X. Wu, N. Le Moan, S. Takimoto, G. Mukandala, K. Akassoglou, W. M. Campana, and S. L. Gonias Low-density lipoprotein receptor-related protein 1 is an essential receptor for myelin phagocytosis J. Cell Sci., April 15, 2009; 122(8): 1155 - 1162. [Abstract] [Full Text] [PDF] K. Zurhove, C. Nakajima, J. Herz, H. H. Bock, and P. May {gamma}-Secretase Limits the Inflammatory Response Through the Processing of LRP1 Sci. Signal., November 25, 2008; 1(47): ra15 - ra15. [Abstract] [Full Text] [PDF]

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