Ethanol-induced oxidative stress suppresses generation of peptides for antigen presentation by hepatoma cells

Research output: Contribution to journalArticle

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Abstract

Processing of peptides for antigen presentation is catalyzed by antigen-trimming enzymes, including the proteasome and leucine aminopeptidase. Oxidative stress suppresses proteasome function. We hypothesized that in liver cells, processing of antigenic peptides is altered by ethanol metabolism. To address this issue, soluble extracts of ethanol-metabolizing VL-17A cells treated with 100 mM ethanol or left untreated were incubated with C-extended or N-extended 18-27 HBV core peptides. Peptide cleavage was measured by recovery after HPLC. Ethanol exposure to VL-17A cells increased CYP2E1 and decreased proteasome peptidase activities. The latter effect was prevented by treatment of cells with inhibitors, 4-methylpyrazole and diallyl sulfide. Ethanol treatment of VL-17A cells also reduced the activity of leucine aminopeptidase (LAP). Consequently, cleavage of both C-extended and N-extended peptides by cytosolic extracts was suppressed by pretreatment of cells with ethanol. Treatment of cells with interferon gamma, which enhances proteasome activity, did not reverse the effects of ethanol. Ethanol exerted similar effects on WIFB cells, indicating that its effects are not unique to one cell type. Conclusion: Ethanol metabolism suppresses activities of antigen-trimming enzymes, thereby decreasing the cleavage of C-extended and N-extended peptides. This defect may potentially result in decreased MHC class I-restricted antigen presentation on virally infected liver cells.

Original languageEnglish (US)
Pages (from-to)53-61
Number of pages9
JournalHepatology
Volume45
Issue number1
DOIs
StatePublished - Jan 1 2007

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Antigen Presentation
Hepatocellular Carcinoma
Oxidative Stress
Ethanol
Peptides
Proteasome Endopeptidase Complex
Leucyl Aminopeptidase
Antigens
Cytochrome P-450 CYP2E1
Histocompatibility Antigens Class I
Liver
Enzymes
Interferon-gamma
Peptide Hydrolases
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Hepatology

Cite this

Ethanol-induced oxidative stress suppresses generation of peptides for antigen presentation by hepatoma cells. / Osna, Natalia A; White, Ronda L.; Todero, Sandra; McVicker, Benita L; Thiele, Geoffrey Milton; Clemens, Dahn L; Tuma, Dean J.; Donohue, Terrence.

In: Hepatology, Vol. 45, No. 1, 01.01.2007, p. 53-61.

Research output: Contribution to journalArticle

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abstract = "Processing of peptides for antigen presentation is catalyzed by antigen-trimming enzymes, including the proteasome and leucine aminopeptidase. Oxidative stress suppresses proteasome function. We hypothesized that in liver cells, processing of antigenic peptides is altered by ethanol metabolism. To address this issue, soluble extracts of ethanol-metabolizing VL-17A cells treated with 100 mM ethanol or left untreated were incubated with C-extended or N-extended 18-27 HBV core peptides. Peptide cleavage was measured by recovery after HPLC. Ethanol exposure to VL-17A cells increased CYP2E1 and decreased proteasome peptidase activities. The latter effect was prevented by treatment of cells with inhibitors, 4-methylpyrazole and diallyl sulfide. Ethanol treatment of VL-17A cells also reduced the activity of leucine aminopeptidase (LAP). Consequently, cleavage of both C-extended and N-extended peptides by cytosolic extracts was suppressed by pretreatment of cells with ethanol. Treatment of cells with interferon gamma, which enhances proteasome activity, did not reverse the effects of ethanol. Ethanol exerted similar effects on WIFB cells, indicating that its effects are not unique to one cell type. Conclusion: Ethanol metabolism suppresses activities of antigen-trimming enzymes, thereby decreasing the cleavage of C-extended and N-extended peptides. This defect may potentially result in decreased MHC class I-restricted antigen presentation on virally infected liver cells.",
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AU - Tuma, Dean J.

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