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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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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 I B 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.
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