Role of endogenous ceruloplasmin in low density lipoprotein oxidation by human U937 monocytic cells.
Open Access
- 1 February 1996
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 97 (3), 884-890
- https://doi.org/10.1172/jci118491
Abstract
Oxidation of lipids and lipoproteins by macrophages is an important event during atherogenesis. Activation of monocytic cells by zymosan and other agonists results in the release of multiple oxidant species and consequent oxidation of LDL. We now show evidence that ceruloplasmin, a copper-containing acute phase reactant, is secreted by zymosan-activated U937 monocytic cells, and that the protein has an important role in LDL oxidation by these cells. In one approach, ceruloplasmin has been shown to exhibit oxidant activity under the appropriate conditions. Exogenous addition of purified human ceruloplasmin stimulates U937 cell oxidation of LDL to nearly the same extent as activation by zymosan. In contrast to previous cell-free experiments (Ehrenwald, E., G.M. Chisom, and P.L. Fox. 1994. Intact human ceruloplasmin oxidatively modifies low density lipoprotein. J. Clin. Invest. 93:1493-1501.) in which ceruloplasmin by itself (in PBS) oxidizes LDL, under the conditions of the current experiments (in RPMI 1640 medium) ceruloplasmin only oxidizes LDL in the presence of cells; the mechanism by which cells overcome the inhibition by medium components has not been ascertained. As further evidence for a role of ceruloplasmin, activation of U937 cells with zymosan induces ceruloplasmin mRNA and ceruloplasmin protein synthesis after a 5-6 h lag that is consistent with that preceding LDL oxidation. Finally, neutralization by a highly specific polyclonal antibody to human ceruloplasmin inhibits LDL oxidation by at least 65%. Moreover, multiple antisense oligodeoxynucleotides targeted to different regions of the ceruloplasmin mRNA block LDL oxidation by up to 95%. The specific action of the antisense oligonucleotides has been verified by showing inhibition of ceruloplasmin synthesis and by the ability of exogenous ceruloplasmin to overcome the inhibition. In summary, these results are consistent with a mechanism in which cell-derived ceruloplasmin participates in oxidation of LDL by U937 monocytic cells. The data also show that cellular factors in addition to ceruloplasmin, possibly active oxygen species and/or lipoxygenases, are essential and act synergistically with ceruloplasmin to oxidize LDL.Keywords
This publication has 55 references indexed in Scilit:
- Serum ferritin and ceruloplasmin as coronary risk factorsEuropean Heart Journal, 1994
- Identification of ceruloplasmin receptors on the surface of human blood monocytes, granulocytes, and lymphocytes.1985
- Absorption, transport, and hepatic metabolism of copper and zinc: special reference to metallothionein and ceruloplasmin.Physiological Reviews, 1985
- Endothelial and smooth muscle cells alter low density lipoprotein in vitro by free radical oxidation.Arteriosclerosis: An Official Journal of the American Heart Association, Inc., 1984
- Purification and characterization of undegraded human ceruloplasminAnalytical Biochemistry, 1980
- Soluble proteins in the human atheroschlerotic plaqueAtherosclerosis, 1979
- Isolation of biologically active ribonucleic acid from sources enriched in ribonucleaseBiochemistry, 1979
- Oxygen-mediated heterogeneity of apo-low-density lipoprotein.Proceedings of the National Academy of Sciences of the United States of America, 1978
- The inhibition of lipid autoxidation by human caeruloplasminBiochemical Journal, 1977
- Measurement of Human Serum Ceruloplasmin by Its p-Phenylenediamine Oxidase ActivityClinical Chemistry, 1970