Published Online
on April 12, 2004

A more recent version of this article appeared on May 4, 2004

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Submitted on June 2, 2003
Revised on January 13, 2004
Accepted on January 21, 2004

High-Density Lipoproteins Neutralize C-Reactive Protein Proinflammatory Activity

Carol Wadham PhD, Nathaniel Albanese BSc, Jane Roberts BSc, Lijun Wang BA, Christopher J. Bagley PhD, Jennifer R. Gamble PhD, Kerry-Anne Rye PhD, Philip J. Barter MD, PhD, Mathew A. Vadas MBBS, PhD, and Pu Xia MD^*

From the Division of Human Immunology, Hanson Institute, Institute of Medical and Veterinary Science (C.W., N.A., J.R., L.W., C.J.B., J.R.G., M.A.V., P.X.), and the University of Adelaide (C.J.B., J.R.G., M.A.V., P.X.), Adelaide, South Australia; and the Lipid Research Group, The Heart Research Institute, Camperdown, NSW (K.-A.R., P.J.B.), Australia.

^* To whom correspondence should be addressed. E-mail: pu.xia{at}imvs.sa.gov.au.

Background--C-reactive protein (CRP), a well-recognized marker of atherosclerosis, has recently been suggested to have a direct proinflammatory effect. The constitutive expression of low levels of CRP in normal plasma suggests the likelihood that a natural factor exists to neutralize the effect of CRP. This factor(s) has not yet been identified.

Method and Results--The proinflammatory effect of CRP was measured by the induction of inflammatory adhesion molecules in human umbilical vein endothelial cells (HUVECs). We show that CRP significantly induced upregulation of adhesion molecules in both protein and mRNA levels. The CRP-induced expression of these inflammatory adhesion molecules was completely suppressed when the cells were preincubated with a physiological concentration (1 mg/mL apolipoprotein A-I) of HDLs derived from human plasma (native HDL) or reconstituted HDL (rHDL) at a very low concentration (0.01 mg/mL apolipoprotein A-I). A novel mechanism of HDL inhibition is likely to operate, because (1) rHDL was 100 times more potent than native HDL, (2) preincubation with HDL and its sustained presence were obligatory, and (3) oxidized 1-palmitoyl-2-linoleoyl-sn-glycero-3-phosphocholine was the fundamental active component.

Conclusions--The CRP-induced upregulation of inflammatory adhesion molecules in HUVECs was completely prevented by HDL via their oxidized phospholipid components.

Key words: lipoproteins • protein • inflammation • atherosclerosis

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