Effects of Tumor Necrosis Factor-α on Peroxidation of Plasma Lipoprotein Lipids in Experimental Animals and Patients

Abstract

Changes in the plasma lipid composition are observed in patients and animals with malignancy and certain other diseases that are consistent with peroxidation of plasma lipoprotein lipids. These changes can be observed with water-suppressed proton (H-1) and carbon-13 (C-13) nuclear magnetic resonance spectroscopy (NMR) and gas chromatography. Gas chromatography provides evidence of a decrease in polyunsaturated fatty acids relative to monounsaturated fatty acids. This evidence is consistent with that observed by C-13 NMR spectroscopy. Mediators for these effects were sought. Cytokines, known to be released in response to malignant tumor cells and to affect lipid metabolism, were injected into normal mice and their effects on the H-1 and C-13 NMR spectra of plasma lipids were observed. Mouse recombinant tumor necrosis factor-alpha (mr-TNF-alpha) significantly decreased the H-1 methyl and methylene lipid linewidths, and the C-13 spectra indicated a decrease in the relative concentration of polyunsaturated fatty acids. The same changes were directly confirmed by gas chromatographic analysis, showing decreases in the amount of linoleic and arachidonic acids and other polyunsaturated fatty acids relative to monounsaturated fatty acids and in the ratio of polyunsaturated to monounsaturated fatty acids. Serial plasma samples from volunteers receiving an infusion of endotoxin showed similar changes in their C-13 NMR spectroscopy at times when peak TNF-alpha values were measured. In addition, in these samples the C-13 NMR spectra showed direct evidence of lipid peroxidation products. These changes were similar to those observed commonly in the plasma of cancer patients. Other cytokines (human recombinant interleukin-1 alpha [hr-IL-1 alpha], hr-IL-2, mouse recombinant interferon-gamma) did not produce these effects. We conclude that TNF-alpha is a mediator (but not necessarily the only one) of changes in plasma lipoprotein lipid composition due to peroxidation and that this is a mechanism for the changes observed in the NMR spectra of plasma from cancer patients and from normal animals injected with TNF-alpha.