Interferons: From Virus Inhibitor to Modulator of Amino Acid and Lipid Metabolism

Borden, Ernest C.; Rosenzweig, I. Bruce; Byrne, Gerald I.

doi:10.1089/jir.1987.7.591

Cited by 12 publications

(3 citation statements)

References 22 publications

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“…Humans or animals excrete tryptophan oxidation products such as kynurenine after administration of IFN-'y (49,50 Finally, experiments presented here as well as elsewhere (8,9) suggest that there may be a fundamental difference between the way nontransformed and transformed cell lines respond to IFN-'y. Both normal and transformed cells can respond to IFN-y by increasing levels of indoleamine 2,3-dioxygenase.…”

Section: Resultssupporting

confidence: 58%

Inhibition of tumor cell growth by interferon-gamma is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide.

Aune¹,

Pogue²

1989

J. Clin. Invest.

100

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Growth of a variety of human tumor cell lines is inhibited by interferon-y (IFN-,y) in vitro. This mechanism is not well understood. The present experiments identify two separate mechanisms which account for the growth inhibitory activity of IFN-'y. Cell lines most sensitive to IFN-'y (inhibited by 10-30 U/ml IFN-y in 3 d) were stimulated by IFN-'y to oxidize tryptophan in media to kynurenine and completely eliminated tryptophan from the culture media after 48-72 h. Addition of L-tryptophan, but not other aromatic amino acids, other essential amino acids, or D-tryptophan, prevented inhibition of cell growth by IFN-'y. The amount of IFN-'y required to yield 50% inhibition of cell growth was directly related to the concentration of L-tryptophan in culture media and increased from -3 to 600 U/ml as the concentration of tryptophan in the media was increased from 25 to 1,000 MM. By contrast, inhibition of growth of the cell lines, BT20 and HT29, was not prevented by addition of tryptophan. Inhibition by IFN-y (100-300 U/ml after 5-6 d) was, however, completely prevented by addition of two inhibitors of adenosine diphosphate-ribosyl transferase (ADP-RT), 3-aminobenzamide or nicotinamide. Activity of ADP-RT was increased in these cell lines after addition of IFN-y. ADP-RT catalyzes the incorporation of the ADP moiety of nicotinamide adenine dinucleotide (NAD) into proteins and causes depletion of intracellular NAD. All tumor cell lines tested had reduced levels of intracellular NAD after treatment with IFN-'y and loss of NAD preceded inhibition of cell growth by 12-24 h. Inhibitors of IFN-y-mediated inhibition of cell growth prevented loss of levels of intracellular NAD. Generation of reactive oxygen species lead to DNA strand breaks which result in activation of ADP-RT. Increased DNA strand breaks were induced in BT20 and HT29 cells but not ME180 and A549 celIs after culture with IFN-'y. The two enzymes known to catalyze the decyclization of tryptophan to kynurenine require superoxide anion for activity.

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Section: Resultssupporting

confidence: 58%

Inhibition of tumor cell growth by interferon-gamma is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide.

Aune¹,

Pogue²

1989

J. Clin. Invest.

100

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“…(IFN-ften,*) is a synthetic recombinant interferon with many of the immunomodulatory effects of the parent compound, IFN-/3. 2 However, IFN-Aero has less toxicity and is well tolerated when administered for longer periods of time. IFN-ften,,,.…”

Section: The Effect Of Interferon On the Metabolism Of Ldlsmentioning

confidence: 99%

The effect of interferon on the metabolism of LDLs.

Schectman

Kaul

Mueller

et al. 1992

Arterioscler Thromb

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Interferons have been shown to lower low density lipoprotein (LDL) cholesterol concentrations by 20-50%. To evaluate the effect of interferons on LDL metabolic behavior in individuals with normal and mildly elevated LDL cholesterol levels, autologous LDL labeled with '"I was administered to subjects at baseline and during interferon treatment Interferon beta^^,, (IFN-ft^.,,) was administered intravenously at 4.5 x 10' units daily for at least 3 weeks before the start of kinetic study and continued for an additional 2 weeks. Results were analyzed by using a multicompartmental model that allows for two intravascular LDL compartments. In normal subjects, TFN-fi mttIM reduced LDL cholesterol and apolipoprotein (apo) B levels by 25% and 27%, respectively (p<0.05); LDL apo B synthesis was decreased by 59% (p<0.05). In hypercholesterolemic subjects, IFN-^KH,, reduced LDL cholesterol levels by 38% (p<0.05); however, apo B concentrations and production rates were not significantly decreased. Clearance of LDL from the first intravascular apo B pool was markedly reduced in these subjects, resulting in a shift in the distribution of LDL apo B from the second to the first intravascular LDL apo B pool. We conclude that interferon's actions on LDL metabolism differ in normocholesterolemic and hypercholesterolemic subjects. In normal subjects, interferon decreased LDL cholesterol and apo B levels through a reduction in the LDL apo B production rate. However, in hypercholesterolemic subjects, interferon reduced LDL cholesterol by altering the distribution of apo B mass between LDL subspecies. ( lesterol of 20% and 50% at the two doses studied, 4.5xlO 6 and 9.0 xlO 7 units, respectively. 5 Both doses were well tolerated.The mechanism behind the effects of interferons in reducing LDL cholesterol and apo B concentrations is unknown. Administration of both interferon gamma and alfa inhibits hepatic and lipoprotein lipase activity, enzymes necessary for the synthesis of LDL from very low density lipoprotein (VLDL).46 Inhibition of this pathway may result in decreased synthesis of LDL. On the other hand, interferons may act as important modulators of cellular protein synthesis by upregulating LDL receptors and enhancing LDL clearance. Because LDL synthetic and catabolic rates are abnormal in hypercholesterolemic subjects, the extent to which interferon affects LDL kinetic behavior may also depend on the presence or absence of normal lipoprotein metabolism. The effect of interferon on individuals with hypercholesterolemia has not been studied. The purpose of this study was to evaluate the effect of recombinant human IFN-fte,,,* on LDL composition and metabolism when administered to normal and mildly hypercholesterolemic subjects. Methods SubjectsKinetic studies were performed before and after intravenous administration of IFM-fte^ injections to 10 subjects. Six had mild hypercholesterolemia with LDL

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“…The identification of the causal genetic variant underlying this association and its function remain to be determined; however, given the genomic location of the associated SNPs, the causal variant is likely to influence levels or activity of one or both of these IFN-lambdas. Treatment with type 1 IFNs has been shown to affect the metabolism of LDL, 27,28 resulting in a marked decline in serum LDL cholesterol levels. Little is known about the effect of type III IFNs on lipid metabolism.…”

mentioning

confidence: 99%

Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection

Li¹,

Lao²,

Tillmann

et al. 2010

Hepatology

110

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Recently, genetic polymorphisms occurring in the interferon (IFN)-lambda gene region were associated with response to IFN-based treatment of hepatitis C infection. Both infection with the hepatitis C virus and IFN therapy are associated with decreased serum cholesterol and high cholesterol has been associated with increased likelihood to respond to IFN. We sought to determine if the IFN-lambda gene variant was also associated with serum lipid levels in chronic hepatitis C patients. We compared genotypes of the rs12979860 polymorphism, located proximal to the IL28 gene, with serum lipid and apolipoprotein levels in 746 subjects with chronic hepatitis C virus infection, not currently undergoing treatment, using multivariable analysis of variance. Levels of total cholesterol (P 5 6.0 3 10 24 ), apolipoprotein B (P 5 1.3 3 10 26) and low-density lipoprotein (LDL) cholesterol (P 5 8.9 3 10 210 ) were significantly higher in subjects carrying the rs12979860 CC responder genotype compared with those with the CT or TT genotype. Levels of triglycerides (P 5 0.03), apolipoprotein A-I (P 5 0.06), and apolipoprotein E (P 5 0.01) were slightly lower in the rs12979860 CC genotype group, whereas levels of high-density lipoprotein cholesterol (P 5 0.78) and apolipoprotein C-III (P 5 0.74) did not vary by rs12979860 genotype. Conclusion: Our results suggest that low levels of LDL cholesterol in chronic hepatitis C patients may be a marker of host endogenous IFN response to hepatitis C and that subjects with the rs12979860 CC responder genotype may have a lower endogenous IFN response to the virus. (HEPATOLOGY 2010;51:1904-1911

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Interferons: From Virus Inhibitor to Modulator of Amino Acid and Lipid Metabolism

Cited by 12 publications

References 22 publications

Inhibition of tumor cell growth by interferon-gamma is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide.

Inhibition of tumor cell growth by interferon-gamma is mediated by two distinct mechanisms dependent upon oxygen tension: induction of tryptophan degradation and depletion of intracellular nicotinamide adenine dinucleotide.

The effect of interferon on the metabolism of LDLs.

Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection

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