Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

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

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

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.

References

  • Abittan CS, Lieber CS . 1999 Curr. Treat Options Gastroenterol. 2: 72–80

  • Adams JM, Cory S . 2001 Trends Biochem. Sci. 26: 61–66

  • Benedetti A, Brunelli E, Risicato R, Cilluffo T, Jezequel AM, Orlandi F . 1988 J. Hepatol. 6: 137–143

  • Bird G . 1994 Acta. Gastroenterol. Belg. 57: 255–259

  • Chang YC, Xu YH . 2000 Cell Res. 10: 233–242

  • Chen J, Bao H, Sawyer S, Kunos G, Gao B . 1997 Biochem. Biophys. Res. Commun. 239: 666–669

  • Chen J, Ishac EJ, Dent P, Kunos G, Gao B . 1998 Biochem. J. 334: 669–676

  • Chen J, Kunos G, Gao B . 1999a FEBS Lett. 457: 162–168

  • Chen MC, Hsu TL, Luh TY, Hsieh SL . 2000 J. Biol. Chem. 275: 38794–38801

  • Chen RH, Chang MC, Su YH, Tsai YT, Kuo ML . 1999b J. Biol. Chem. 274: 23013–23019

  • Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, Taub R . 1996 Science 274: 1379–1383

  • Deaciuc IV, Alappat JM, McDonough KH, D'Souza NB . 1996 Alcohol. Clin. Exp. Res. 20: 293–301

  • Deaciuc IV, Fortunato F, D'Souza N, Hill D, McClain C . 2001 Hepatol. Res. 19: 306–324

  • Diehl AM . 1989 Med. Clin. North Am. 73: 815–830

  • Diehl AM . 1999a Alcohol. Clin. Exp. Res. 23: 1419–1424

  • Diehl AM . 1999b Clin. Biochem. 32: 571–578

  • Ezure T, Sakamoto T, Tsuji H, Lunz III JG, Murase N, Fung JJ, Demetris AJ . 2000 Am. J. Pathol. 156: 1627–1639

  • Fontanilla CV, Faunce DE, Gregory MS, Messingham KA, Durbin EA, Duffner LA, Kovacs EJ . 2000 Alcohol. Clin. Exp. Res. 24: 1392–1399

  • Fuchs D, Gruber A, Uberall F, Wachter H . 1994 Immunol. Today 15: 496

  • Galun E, Zeira E, Pappo O, Peters M, Rose-John S . 2000 FASEB J. 14: 1979–1987

  • Goldin RD, Hunt NC, Clark J, Wickramasinghe SN . 1993 J. Pathol. 171: 73–76

  • Gonzalez-Quintela A, Dominguez-Santalla MJ, Perez LF, Vidal C, Lojo S, Barrio E . 2000 Cytokine 12: 1437–1440

  • Grad J, Zeng X, Boise L . 2000 Curr. Opin. Oncol. 12: 543–549

  • Hall PD . 1994 Alcohol. Suppl. 2: 303–313

  • Halsted CH, Villanueva J, Chandler CJ, Stabler SP, Allen RH, Muskhelishvili L, James SJ, Poirier L . 1996 Hepatology 23: 497–505

  • Hecht N, Pappo O, Shouval D, Rose-John S, Galun E, Axelrod JH . 2001 Mol. Ther. 3: 683–687

  • Hill DB, Marsano L, Cohen D, Allen J, Shedlofsky S, McClain CJ . 1992 J. Lab. Clin. Med. 119: 547–552

  • Hong F, Nguyrn VA, Gao B . 2001 FASEB J. 15: 1595–1597

  • Hong F, Nguyen VA, Shen X, Kunos G, Gao B . 2000 Biochem. Biophys. Res. Commun. 279: 974–979

  • Kamimura S, Tsukamoto H . 1995 Hepatology 22: 1304–1309

  • Kim W, Hong F, Jaruga B, Hu Z, Fan S, Liang J, Gao B . 2001 FASEB J. 15: in press

  • Kovalovich K, DeAngelis RA, Li W, Furth EE, Ciliberto G, Taub R . 2000 Hepatology 31: 149–159

  • Kovalovich K, Li W, DeAngelis R, Greenbaum LE, Ciliberto G, Taub R . 2001 J. Biol. Chem. 276: 26605–26613

  • Kuo ML, Chuang SE, Lin MT, Yang SY . 2001 Oncogene 20: 677–685

  • Kurose I, Higuchi H, Miura S, Saito H, Watanabe N, Hokari R, Hirokawa M, Takaishi M, Zeki S, Nakamura T, Ebinuma H, Kato S, Ishii H . 1997 Hepatology 25: 368–378

  • Lacronique V, Mignon A, Fabre M, Viollet B, Rouquet N, Molina T, Porteu A, Henrion A, Bouscary D, Varlet P, Joulin V, Kahn A . 1996 Nat. Med. 2: 80–86

  • Laso FJ, Iglesias-Osma C, Ciudad J, Lopez A, Pastor I, Orfao A . 1999 Alcohol. Clin. Exp. Res. 23: 1306–1311

  • Maddrey WC . 2000 Clin. Liver Dis. 4: 115–131 vii

  • Martinez F, Abril ER, Earnest DL, Watson RR . 1992 Alcohol 9: 455–458

  • McClain CJ, Barve S, Deaciuc I, Kugelmas M, Hill D . 1999 Semin. Liver Dis. 19: 205–219

  • Mi LJ, Mak KM, Lieber CS . 2000 Alcohol. Clin. Exp. Res. 24: 207–212

  • Panesar N, Tolman K, Mazuski JE . 1999 J. Surg. Res. 85: 251–258

  • Pastorino JG, Hoek JB . 2000 Hepatology 31: 1141–1152

  • Pennington HL, Hall PM, Wilce PA, Worrall S . 1997 J. Gastroenterol. Hepatol. 12: 305–313

  • Rashid A, Wu TC, Huang CC, Chen CH, Lin HZ, Yang SQ, Lee FY, Diehl AM . 1999 Hepatology 29: 1131–1138

  • Rollwagen FM, Yu ZY, Li YY, Pacheco ND . 1998 Clin. Immunol. Immunopathol 89: 205–213

  • Sasaki Y, Wands JR . 1994 Biochem. Biophys. Res. Commun. 199: 403–409

  • Sheron N, Bird G, Goka J, Alexander G, Williams R . 1991 Clin. Exp. Immunol. 84: 449–453

  • Slomiany A, Piotrowski E, Grabska M, Piotrowski J, Slomiany BL . 1999 Alcohol. Clin. Exp. Res. 23: 334–343

  • Tuma DJ, Todero SL, Barak-Bernhagen M, Sorrell MF . 1996 Alcohol. Clin. Exp. Res. 20: 579–583

  • Walsh K, Alexander G . 2000 Postgrad. Med. J. 76: 280–286

  • Ward NS, Waxman AB, Homer RJ, Mantell LL, Einarsson O, Du Y, Elias JA . 2000 Am. J. Respir. Cell. Mol. Biol. 22: 535–542

  • Yacoub LK, Fogt F, Griniuviene B, Nanji AA . 1995 Alcohol. Clin. Exp. Res. 19: 854–859

  • Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG . 1999 Gastroenterology 117: 942–952

  • Zhang B, Zhang D, Ren H . 2000 Zhonghua Gan Zang Bing Za Zhi 8: 215–217

  • Zhao M, Laissue JA, Zimmermann A . 1997 Virchows Arch 431: 337–344

Download references

Acknowledgements

This work is supported by National Institutes of Health intramural program and grant R01AA12637.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bin Gao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1205016

Keywords

This article is cited by

Search

Quick links