This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 29/3/356    most recent ATVBAHA.108.173799v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by von Schlieffen, E. Articles by Bochkov, V. N. Search for Related Content PubMed PubMed Citation Articles by von Schlieffen, E. Articles by Bochkov, V. N. Related Collections Related Article

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:356.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Multi-Hit Inhibition of Circulating and Cell-Associated Components of the Toll-Like Receptor 4 Pathway by Oxidized Phospholipids

Elena von Schlieffen; Olga V. Oskolkova; Gernot Schabbauer; Florian Gruber; Stephan Blüml; Melinda Genest; Alexandra Kadl; Claudia Marsik; Sylvia Knapp; Jesse Chow; Norbert Leitinger; Bernd R. Binder; Valery N. Bochkov

From the Departments of Vascular Biology and Thrombosis Research (E.v.S., O.V.O., G.S., B.R.B., V.N.B.), Dermatology (F.G.), Internal Medicine III (S.B.), Medical and Chemical Laboratory Diagnostics (C.M.), and Internal Medicine I (S.K.), Medical University of Vienna, Austria; Eisai Research Institute (M.G., J.C.), Andover, Mass; and the Cardiovascular Research Center (A.K., N.L.), University of Virginia, Charlottesville.

Correspondence to Valery Bochkov, PhD, Center for Biomolecular Medicine and Pharmacology, Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria. E-mail valery.bochkov{at}meduniwien.ac.at

Objective— Oxidized phospholipids (OxPLs) that are abundant in atherosclerotic lesions are increasingly recognized as context-dependent lipid mediators demonstrating both pro- and antiinflammatory activities. Molecular mechanisms of their effects are largely unknown. Here we present novel information on the mechanisms whereby OxPLs modulate activation of TLR4 by lipopolysaccharide (LPS).

Methods and Results— We show, using several cell types and various inflammatory genes as readouts, that different classes and molecular species of OxPLs do not stimulate TLR4 but exert prominent inhibitory effects on LPS-induced reactions. Our data demonstrate that binding of OxPLs to the LPS-binding protein (LBP) and CD14 prevents recognition of LPS by these proteins, thus impairing activation of TLR4. In addition, OxPLs inhibited LBP- and CD14-independent activation of TLR4 by the synthetic TLR4 agonist E6020 indicating that in parallel with LBP and CD14, OxPLs target cell-associated steps in TLR4 cascade.

Conclusions— Our data suggest that OxPLs inhibit action of LPS via a multi-hit mechanism. These results support the notion that OxPLs are endogenous inhibitors of TLR4 produced in response to oxidative stress.

In this work, open questions concerning the regulation of TLR4 by oxidized phospholipids (OxPLs) were addressed. The data demonstrate that OxPLs simultaneously inhibit several steps in LPS recognition and activation of TLR4 signaling.

Key Words: oxidized phospholipids • lipopolysaccharide • TLR4 • LBP • CD14

Related Article:

Oxidized Phospholipid Inhibition of LPS-Signaling: A Good Side to the Bad Guys?

Clett Erridge
Arterioscler Thromb Vasc Biol 2009 29: 337-338. [Extract] [Full Text] [PDF]

This article has been cited by other articles:

				A. H. Morgan, V. Dioszeghy, B. H. Maskrey, C. P. Thomas, S. R. Clark, S. A. Mathie, C. M. Lloyd, H. Kuhn, N. Topley, B. C. Coles, et al. Phosphatidylethanolamine-esterified Eicosanoids in the Mouse: TISSUE LOCALIZATION AND INFLAMMATION-DEPENDENT FORMATION IN Th-2 DISEASE J. Biol. Chem., August 7, 2009; 284(32): 21185 - 21191. [Abstract] [Full Text] [PDF]

				C. Erridge Oxidized Phospholipid Inhibition of LPS-Signaling: A Good Side to the Bad Guys? Arterioscler Thromb Vasc Biol, March 1, 2009; 29(3): 337 - 338. [Full Text] [PDF]