Abstract
Elevation of serum interleukin-6 (IL-6) levels is always associated with alcoholic liver disease (ALD), but the significance of such elevation is not clear. Here we show that chronic ethanol consumption induces significant apoptosis in the liver of IL-6 (−/−) mice but not IL-6 (+/+) mice. IL-6 (−/−) hepatocytes are more susceptible to ethanol- and tumor necrosis factor α- (TNFα-) induced apoptotic killing, which can be corrected by IL-6. Expression of both anti-apoptotic (such as Bcl-2 and Bcl-xL) and proapoptotic (such as Bax) proteins is markedly elevated in the liver of human ALD and chronically ethanol-fed IL-6 (+/+) mice. On the contrary, induction of Bcl-2 and Bcl-xL is not observed in the liver of chronically ethanol-fed IL-6 (−/−) mice, whereas expression of Bax protein remains elevated. Injection of IL-6 markedly induces expression of Bcl-2 and Bcl-xL but not Bax in the liver. Finally, high concentrations of ethanol inhibit IL-6-activated anti-apoptotic signal, but increasing the concentrations of IL-6 is able to overcome such inhibitory effect. These findings suggest that elevated serum IL-6 levels in ALD may overcome the inhibitory effect of ethanol on IL-6-mediated anti-apoptotic signals and prevent alcohol-induced hepatic apoptosis by induction of Bcl-2 and Bcl-xL.
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Abbreviations
- ALD:
-
alcoholic liver disease
- Bax:
-
Bcl-2-associated X protein
- Bcl-2:
-
B cell lymphoma-2 associated oncogene
- ETOH:
-
ethanol
- TNFα:
-
tumor necrosis factor α
- IL-6:
-
interleukin-6
- IL-6 (−/−):
-
IL-6 null
- IL-6 (+/+):
-
IL-6 wild type
- STAT3:
-
signal transducer and activator transcription factor 3.
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Acknowledgements
This work is supported by National Institutes of Health intramural program and grant R01AA12637.
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Hong, F., Kim, WH., Tian, Z. et al. Elevated interleukin-6 during ethanol consumption acts as a potential endogenous protective cytokine against ethanol-induced apoptosis in the liver: involvement of induction of Bcl-2 and Bcl-xL proteins. Oncogene 21, 32–43 (2002). https://doi.org/10.1038/sj.onc.1205016
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DOI: https://doi.org/10.1038/sj.onc.1205016
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