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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.
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Submitted December 6, 2007
Accepted March 18, 2008
Regulation of tumor necrosis factor receptor-1 and the IKK-NF- B pathway by LDL receptor-related protein explains the anti-inflammatory activity of this receptor
Alban Gaultier, Sanja Arandjelovic, Sherry Niessen, Cheryl D Overton, MacRae F Linton, Sergio Fazio, W Marie Campana, Benjamin F Cravatt III, and Steven L Gonias*
Department of Pathology, University of California San Diego School of Medicine, La Jolla, CA, United States
Department of Chemical Biology and the Skaggs Institute for Chemical Biology, Scripps Research institute, La Jolla, CA, United States
the Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, United States
Department of Anesthesiology, University of California San Diego School of Medicine, La Jolla, CA, United States
* Corresponding author; email: sgonias{at}ucsd.edu.
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 IKK-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 IKK-NF-B pathway.
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