scholarly journals Effects of tumor necrosis factor-alpha on peroxidation of plasma lipoprotein lipids in experimental animals and patients

Blood ◽  
1992 ◽  
Vol 80 (12) ◽  
pp. 3217-3226
Author(s):  
J McDonagh ◽  
ET Fossel ◽  
RL Kradin ◽  
SM Dubinett ◽  
M Laposata ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Nmr Spectra ◽  
Monounsaturated Fatty Acids ◽  
Plasma Lipoprotein ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Lipoprotein Lipids ◽  
Factor Alpha ◽  
Necrosis Factor

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.

scholarly journals Effects of tumor necrosis factor-alpha on peroxidation of plasma lipoprotein lipids in experimental animals and patients

Blood ◽  
1992 ◽  
Vol 80 (12) ◽  
pp. 3217-3226 ◽  
Author(s):  
J McDonagh ◽  
ET Fossel ◽  
RL Kradin ◽  
SM Dubinett ◽  
M Laposata ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Nmr Spectra ◽  
Monounsaturated Fatty Acids ◽  
Plasma Lipoprotein ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Lipoprotein Lipids ◽  
Factor Alpha ◽  
Necrosis Factor

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.

Tumor necrosis factor-alpha inhibits lipid and lipoprotein transport by Caco-2 cells

1995 ◽  
Vol 269 (6) ◽  
pp. G953-G960 ◽  
Author(s):  
M. Mehran ◽  
E. Seidman ◽  
R. Marchand ◽  
C. Gurbindo ◽  
E. Levy
Keyword(s):  
Lipid Metabolism ◽  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Low Density Lipoproteins ◽  
Tnf Alpha ◽  
Low Density ◽  
Necrosis Factor Alpha ◽  
Apo B ◽  
Factor Alpha ◽  
Necrosis Factor

Cytokines, important mediators of inflammation, have been shown to cause disturbances in circulating and hepatic lipid metabolism. Although the intestine plays a major role in dietary fat transport and largely contributes to plasma lipoproteins, the effects of cytokines on intestinal lipid handling remain unknown. In the present study, the modulation of lipid, apoprotein, and lipoprotein synthesis and secretion by tumor necrosis factor-alpha (TNF-alpha) was investigated in Caco-2 cells. Highly differentiated and polarized cells (20 days in culture) were incubated for 20 h with recombinant human TNF-alpha (100-500 ng/ml). No cytotoxic effect of TNF-alpha cells was observed, as indicated by the determinations of Caco-2 cell viability and monolayer transepithelial resistance. Moreover, no differences in cell maturation (sucrase activity) or cell proliferation ([3H]thymidine incorporation and cell cycle analysis) were detected between treated and control cultures. Significant inhibition of lipid secretion by TNF-alpha was observed, with the greatest reduction at 500 ng/ml. TNF-alpha significantly decreased Caco-2 cell secretion of phospholipids (22%), triglycerides (30%), and cholesteryl ester (37%). It also significantly diminished the export of newly synthesized low-density lipoproteins (LDL; 20%) and high-density lipoproteins (HDL; 13%), with a lesser effect on very low-density lipoproteins (VLDL; 3%). The lipid composition of these lipoproteins was minimally affected. De novo synthesis of apo A-I, apo B-100, and apo B-48 was also markedly reduced by TNF-alpha. Sphingomyelinase activity was not increased and cell content of sphingomyelin was not altered, suggesting that inhibitory effects on lipid and apoprotein of TNF-alpha were not mediated by the ceramide pathway. Our results indicate that TNF-alpha may play a role in modulating intestinal lipid metabolism, thus affecting circulating lipoproteins.

scholarly journals Increased adipose tissue secretion of interleukin-6, but not of leptin, plasminogen activator inhibitor-1 or tumour necrosis factor alpha, in Graves' hyperthyroidism

2002 ◽  
pp. 607-611 ◽  
Author(s):  
H Wahrenberg ◽  
A Wennlund ◽  
J Hoffstedt
Keyword(s):  
Adipose Tissue ◽  
Plasminogen Activator Inhibitor ◽  
Tumour Necrosis Factor Alpha ◽  
Tnf Alpha ◽  
Plasminogen Activator Inhibitor 1 ◽  
Necrosis Factor Alpha ◽  
Factor Alpha ◽  
Activator Inhibitor ◽  
Necrosis Factor ◽  
Pai 1

OBJECTIVE: This study was designed to investigate adipose tissue secretion of interleukin-6 (IL-6), leptin, tumour necrosis factor alpha (TNF-alpha) and plasminogen activator inhibitor-1 (PAI-1) in Graves' hyperthyroidism. DESIGN: We studied 10 patients before and during (after 8 weeks) anti-thyroid treatment for Graves' hyperthyroidism and 16 healthy, euthyroid control subjects. METHODS: Plasma levels of thyroid hormones and serum/plasma levels of IL-6, leptin, TNF-alpha and PAI-1 were analysed. Subcutaneous fat biopsies were taken for subsequent measurement of IL-6, leptin, TNF-alpha and PAI-1 protein secretion. RESULTS: In patients with Graves' disease, the anti-thyroid treatment resulted in significant reductions of plasma thyroxine and triiodothyronine levels. No differences in serum concentration or adipose tissue secretion of leptin or TNF-alpha were observed either before, as compared with during, anti-thyroid treatment, or in comparison with euthyroid controls. In contrast, plasma PAI-1 activity, but not adipose tissue secretion of PAI-1, was increased both in Graves' disease before as compared with during anti-thyroid treatment (P=0.01) and in thyrotoxic patients compared with euthyroid controls (P=0.0001). Finally, adipose secretion of IL-6 was increased both before (8-fold, P=0.001) and during (6-fold, P<0.0001) treatment as compared with control subjects. Accordingly, serum concentration of IL-6 was also increased by about 50% in thyrotoxic patients as compared with healthy controls (P=0.03). CONCLUSIONS: In Graves' hyperthyroidism regardless of thyroid status, adipose tissue secretion of IL-6, but not of leptin, TNF-alpha or PAI-1, is markedly increased in comparison with euthyroid controls. This suggests that autoimmune thyroidal disorder may regulate adipose tissue release of IL-6.

The mitogenic response to tumor necrosis factor alpha requires c-Jun/AP-1

1993 ◽  
Vol 13 (7) ◽  
pp. 4284-4290
Author(s):  
M A Brach ◽  
H J Gruss ◽  
C Sott ◽  
F Herrmann
Keyword(s):  
Tumor Necrosis ◽  
Growth Stimulation ◽  
Myelogenous Leukemia ◽  
Tnf Alpha ◽  
Mitogenic Response ◽  
Necrosis Factor Alpha ◽  
Acute Myelogenous ◽  
Factor Alpha ◽  
Necrosis Factor

In the present study, we addressed the role of the c-jun proto-oncogene in the mitogenic response of human fibroblasts and primary acute myelogenous leukemia blasts to tumor necrosis factor alpha (TNF-alpha). Our data indicate that TNF-alpha treatment of these cells is associated with transcriptional activation of c-jun, resulting in accumulation of c-jun mRNA and protein expression. In order to elucidate the role of c-Jun/AP-1 in TNF-mediated growth stimulation, the antisense (AS) technique was used. Uptake studies of oligonucleotides were performed with fibroblasts, demonstrating that incorporation of oligomers was maximal at 4 h. Oligodeoxynucleotides remained stable in these cells for up to 24 h. Treatment of fibroblasts with the AS oligonucleotide resulted in intracellular duplex formation followed by an efficient translation blockade of c-Jun/AP-1. In contrast, sense (S) and nonsense (NS) oligodeoxynucleotides failed to form intracellular duplexes and also did not interfere with translation of c-Jun/AP-1, suggesting specific elimination of c-Jun/AP-1 by the AS oligomer. Fibroblasts cultured in the presence of the AS oligonucleotide but not those cultured in the presence of the S or NS oligonucleotide failed to respond proliferatively to TNF-alpha. These findings could be confirmed by experiments with primary acute myelogenous leukemia blasts, which also demonstrated that TNF-induced growth stimulation required c-Jun/AP-1 function. Taken together, our results indicate that activation of c-Jun/AP-1 plays a pivotal role in the signaling cascade initiated by TNF, which leads to a proliferative response of its target cells.

NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1

1994 ◽  
Vol 14 (10) ◽  
pp. 6561-6569
Author(s):  
L Klampfer ◽  
T H Lee ◽  
W Hsu ◽  
J Vilcek ◽  
S Chen-Kiang
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis Factor Alpha ◽  
Tumor Necrosis ◽  
Interleukin 1 ◽  
Human Fibroblasts ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Normal Human ◽  
Factor Alpha ◽  
Necrosis Factor

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

scholarly journals Endothelial cytosolic proteins bind to the 3' untranslated region of endothelial nitric oxide synthase mRNA: regulation by tumor necrosis factor alpha.

1997 ◽  
Vol 17 (10) ◽  
pp. 5719-5726 ◽  
Author(s):  
J Alonso ◽  
L Sánchez de Miguel ◽  
M Montón ◽  
S Casado ◽  
A López-Farré
Keyword(s):  
Endothelial Nitric Oxide Synthase ◽  
Tumor Necrosis ◽  
Tnf Alpha ◽  
Necrosis Factor Alpha ◽  
Cytosolic Proteins ◽  
Enos Mrna ◽  
Factor Alpha ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Necrosis Factor

Changes in endothelial nitric oxide synthase (eNOS) expression may be involved in the endothelium-dependent vasorelaxation dysfunction associated with several vascular diseases. In the present work, we demonstrate that eNOS mRNA contains a previously undescribed cis element in the 3' untranslated region (3' UTR). A U+C-rich segment in the 3' UTR is critical in complex formation with bovine aortic endothelial cell cytosolic proteins. Tumor necrosis factor alpha (TNF-alpha), which destabilizes eNOS mRNA, increased the binding activity of the cytosolic proteins in a time-dependent manner. These data suggest that endothelial cytosolic proteins bind to the 3' UTR of eNOS mRNA. These proteins may play a role in TNF-alpha-induced eNOS mRNA destabilization.

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