Native LDL potentiate TNF alpha and IL-8 production by human mononuclear cells.
Native LDL (nLDL) increases expression of adhesion molecules on endothelial cells through induction of Ca(2+) mobilization. Ca(2+) 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 alpha (TNF alpha) 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 Ca(2+) mobilization, because: a) nLDL induced a sustained pattern of repetitive Ca(2+) transients in human PBMC; b) the Ca(2+) chelator fura 2-acetoxymethyl ester, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, an intracellular Ca(2+) chelator, inhibited the potentiating effect of nLDL on LPS-induced cytokine synthesis; c) induction of Ca(2+) 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 Ca(2+) mobilization. This may represent an important pathogenetic mechanism in atherogenesis induced by hyperlipoproteinemia.
Netea
Mihai G
MG
Department 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. m.netea@aig.azn.nl
Kullberg
Bart Jan
BJ
Demacker
Pierre N M
PN
Jacobs
Liesbeth E H
LE
Verver-Jansen
Trees J G
TJ
Hijmans
Anneke
A
van Tits
Lambertus H J
LH
Hoenderop
Joost G J
JG
Willems
Peter H G M
PH
Van der Meer
Jos W M
JW
Stalenhoef
Anton F H
AF
D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D016209:Interleukin-8; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D014409:Tumor Necrosis Factor-alpha; D002118:Calcium