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Journal of Lipid Research, Vol. 43, 1065-1071, July 2002
Copyright © 2002 by Lipid Research, Inc.

Native LDL potentiate TNF and IL-8 production by human mononuclear cells

Mihai G. Netea^*, Bart Jan Kullberg^*, Pierre N. M. Demacker^*, Liesbeth E. H. Jacobs^*, Trees J. G. Verver-Jansen^*, Anneke Hijmans^*, Lambertus H. J. van Tits^*, Joost G. J. Hoenderop, Peter H. G. M. Willems, Jos W. M. Van der Meer^* and Anton F. H. Stalenhoef^1,*

^* Departments of Medicine, University Medical Center St. Radboud, Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands
Biochemistry, University Medical Center St. Radboud, Geert Grooteplein 8, 6500 HB Nijmegen, The Netherlands

¹ To whom correspondence should be addressed. e-mail: m.netea{at}aig.azn.nl

Native LDL (nLDL) increases expression of adhesion molecules on endothelial cells through induction of Ca²⁺ mobilization. Ca²⁺ mobilization is also involved in the induction of proinflammatory cytokines, important mediators involved in atherogenesis. The aim of the study was to evaluate the capacity of nLDL to affect spontaneous and lipopolysaccharide (LPS)-stimulated cytokine production. Preincubation of human peripheral blood mononuclear cells (PBMC) with nLDL for 24 h did not influence spontaneous production of tumor necrosis factor (TNF) or interleukin-8 (IL-8), but significantly potentiated LPS-induced production of these cytokines. nLDL preincubation of PBMC did not increase the expression of the LPS receptors Toll-like receptor-4, CD14, or CD11c/CD18. Potentiation of cytokine production by nLDL was mediated through induction of Ca²⁺ mobilization, because: a) nLDL induced a sustained pattern of repetitive Ca²⁺ transients in human PBMC; b) the Ca²⁺ chelator fura 2-acetoxymethyl ester, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, an intracellular Ca²⁺ chelator, inhibited the potentiating effect of nLDL on LPS-induced cytokine synthesis; c) induction of Ca²⁺ mobilization by thapsigargin potentiated LPS-induced cytokine production.

nLDL are able to potentiate LPS-induced production of cytokines by human PBMC, and this effect is probably mediated through induction of Ca²⁺ mobilization. This may represent an important pathogenetic mechanism in atherogenesis induced by hyperlipoproteinemia.

Abbreviations: BAPTA-AM, the Ca²⁺ chelator fura 2-acetoxymethyl ester, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; IL-8, interleukin-8; LPDP, lipoprotein-depleted plasma; LPS, lipopolysaccharide; PBMC, peripheral blood mononuclear cells; PKC, protein kinase C; TLR4, Toll-like receptor 4; TNF, tumor necrosis factor; TNFbp, TNF binding proteins

Supplementary key words tumor necrosis factor • interleukin-8 • Ca²⁺ mobilization • low density lipoprotein

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