Institut für Ernährungsmedizin

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Effect of low ethanol concentrations on the production and stability of Interferon gamma
(2008) Sauter, Senja; Bode, Christiane
Alcohol is known to modulate the immune system in a complex manner. The effects of alcohol on immune responses vary with acute and chronic exposure as well as depending on the history of alcohol consumption and the blood level of alcohol. The presence or absence of alcohol can affect the cytokine cascade in complex ways. In the current study the immunmodulatory capability of an acute, moderate (1 ?) to high amount (3 ?) of alcohol was tested on isolated Peripheral Blood Mononuclear Cells production of several proinflammatory and antiinflammatory cytokines after incubation for 12 to 72 hours. The most affected cytokine in our model system of isolated human PBMC treated with two different ethanol concentrations was IFN-γ. Its concentration decreased in a highly significant manner in PHA- as well as in LPS-stimulated PBMC when treated with 66 mM ethanol and in a significant manner in PHA-activated PBMC when treated with 22 mM ethanol. The fact that ethanol negatively affects IFN-γ production is supported by several in vivo and in vitro studies by Wagner et al., 1992, Chen et al., 1993, Laso et al., 1997 Waltenbaugh et al., 1998, Starkenburg et al., 2001, Szabo et al., 2001, Dokur et al., 2003. The reduced IFN-γ level observed might be a key factor in explaining comprised immunity seen after chronic alcohol abuse, since together with IL-12, IFN-γ is crucial for the innate and adaptive immune response to viral and bacterial infection (Vicente-Gutierrez et al., 1991, Windle et al., 1993, Szabo 1997, Szabo et al., 1999). As seen in isolated human Peripheral Blood Mononuclear Cells IFN-γ production by IL-12 stimulated NK-92 cells is significantly reduced in the presence of ethanol. However, this decrease did not correlate with decreased phosphorylation and nuclear translocation of STAT4, a central regulator of IFN-γ gene expression. These results indicated that acute alcohol treatment in vitro did not affect intracellular pathways leading to IFN-γ gene expression. These findings paralleled results indicating that the amount of mRNA for IFN-γ synthesis in NK-92 cells is not affected by the applied ethanol concentrations as well. Additionally it was shown within the current work, that the reduced IFN-γ production by NK-92 cells in the presence of ethanol might not be explained by an intracellular accumulation of the IFN-γ protein. The inhibitory action of ethanol on IFN-γ may rather be caused by posttranslational modification once IFN-γ is released by NK-92 cells, since the addition of recombinant human IFN-γ to the cell culture supernatants of ethanol-treated cells led to a decline in the amount of IFN-γ concentration. We therefore hypothesized that ethanol may cause the release of either an IFN-γ-binding or IFN-γ-degrading protein. An increase in soluble IFN-γ receptor as a result of ethanol treatment was not observed. But the addition of mixture of 5 commercially available protease inhibitors counteracted the effect of ethanol treatment, giving us a first hint of IFN-γ-modulatory mechanism, where IFN-γ released by NK-92 cells may be disintegrated by a protease released as consequence of ethanol incubation. To our best knowledge we are the first to demonstrate a posttranslational modification of IFN-γ as a consequence of ethanol incubation. In summary, the present results support the inhibitory role of ethanol on IFN-γ, but are too preliminary to explain the underlying immunmodulatory effect.

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