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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:1133.)
© 2003 American Heart Association, Inc.

Editorials

How Do Oxidized Phospholipids Inhibit LPS Signaling?

Nigel Mackman

From The Scripps Research Institute, Department of Immunology, La Jolla, Calif.

From The Scripps Research Institute, Department of Immunology, 10550 N Torrey Pines Rd, C-204, La Jolla, CA 92037. E-mail nmackman@scripps.edu

An extract of the first 250 words of the full text is provided, because this article has no abstract.

In 1981, Henriksen and coworkers¹ reported that oxidized LDL (oxLDL) induces cholesterol accumulation in macrophages. This observation formed the basis of the hypothesis that oxidation of LDL might be an important step in the atherogenesis process. Many subsequent studies support the oxidative modification hypothesis of atherogenesis.^2–4 However, oxidation of LDL is a complex process. Both the protein and the lipid molecules of LDL can be oxidatively modified resulting in a variety of biologically active molecules. The primary targets of oxidation are the esterified polyunsaturated fatty acids in the phospholipid shell that surrounds the insoluble neutral lipids of the lipoprotein core (Figure 1A). Importantly, atherosclerotic lesions contain antigens recognized by antibodies generated against oxLDL, demonstrating the presence of oxLDL in vivo.^5–7

View larger version (42K): [in this window] [in a new window]   Figure 1. Gene expression induced by mmLDL, oxLDL, and LPS. LDL can undergo mild oxidation or extensive oxidation to produce mmLDL and oxLDL, respectively. mmLDL binds to the LDL receptor as well as an undefined G protein–coupled receptor. mmLDL activates the transcription factors Egr-1, NF-AT, and PPAR and induces expression of the pro-atherogenic genes IL-8, MCP-1, and TF. OxLDL binds to the scavenger receptors SR-BI and CD36. LPS from the outer membrane of Escherichia coli binds to LBP in the serum and is delivered to CD14. The LPS signaling receptor contains TLR4 and MD2. Binding of the intracellular adaptor proteins, MyD88 and Mal, to the cytoplasmic domain of TLR4 activates NF-B, AP-1, and Egr-1 and induces the expression of the pro-inflammatory genes, TNF, IL-8, MCP-1, TF, . . . [Full Text of this Article]

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