Effects of tumor necrosis factor-alpha on peroxidation of plasma
lipoprotein lipids in experimental animals and patients
J McDonagh, ET Fossel, RL Kradin, SM Dubinett, M Laposata and YA Hallaq
Department of Pathology, Beth Israel Hospital, Massachusetts General
Hospital, Boston, MA 02215.
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.
Volume 80,
Issue 12,
pp. 3217-3226,
12/15/1992
Copyright © 1992 by The American Society of Hematology
