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Originally published In Press as doi:10.1074/jbc.M100740200 on May 10, 2001

J. Biol. Chem., Vol. 276, Issue 28, 26605-26613, July 13, 2001
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Interleukin-6 Protects against Fas-mediated Death by Establishing a Critical Level of Anti-apoptotic Hepatic Proteins FLIP, Bcl-2, and Bcl-xL*

Kellen KovalovichDagger §, Wei LiDagger , Robert DeAngelisDagger , Linda E. Greenbaum§, Gennaro Ciliberto||, and Rebecca TaubDagger **

From the Dagger  Department of Genetics, the § Department of Medicine, Division of Gastroenterology, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104 and the || Istituto Ricerce di Biologia Molecolare (IRBM), 00040 Rome, Italy

Previous studies showed that following acute carbon tetrachloride (CCl4) treatment, interleukin-6 null (IL-6-/-) mice develop increased hepatocellular injury, defective regeneration, delayed wound healing, and increased hepatocyte apoptosis. Pretreatment with IL-6 prior to CCl4 reduces injury, hepatocyte apoptosis, and accelerates regeneration in both IL-6-/- and +/+ livers. To demonstrate whether IL-6 can prevent liver injury that involves direct stimulation of hepatocyte apoptosis, IL-6-/- and +/+ mice were treated with the Fas agonist, Jo-2 mAb. At low Fas agonist doses, IL-6+/+ mice developed mild hepatic injury and survived, whereas IL-6-/- mice developed severe apoptotic hepatitis within 12 h and died. Pretreatment with IL-6 improved survival in IL-6-/- mice and reduced injury in both IL-6-/- and +/+ livers. The direct anti-apoptotic effects of IL-6 were demonstrated in vitro as IL-6 decreased Fas-mediated apoptosis in both IL-6-/- and +/+ primary hepatocyte cultures, and suggested that IL-6-/- hepatocytes have a pre-existing defect in anti-apoptotic pathways. After Fas activation, IL-6-/- livers demonstrated evidence of both proximal and distal alterations in the apoptotic pathways including elevated caspase 8 and 3 activation-associated fragments, and loss of cytochrome c staining. IL-6-/- livers had reduced pre-existing protein expression of the anti-apoptotic factors Bcl-2 and Bcl-xL as well as more rapid degradation of FLIP following Fas treatment that appeared to be post-transcriptionally regulated. FLIP is a crucial proximal inhibitor of caspase 8 activation in Fas, tumor necrosis factor, and DR3/DR4-mediated apoptosis, and Bcl-2 and Bcl-xL more downstream anti-apoptotic regulators. IL-6 may function as a critical anti-apoptotic factor in the liver by its ability to establish and maintain an adequate level of FLIP and downstream anti-apoptotic factors.

* This work was supported by University of Pennsylvania Digestive and Liver Center Grant P30 DK50306 and in part by National Institutes of Health Grants 1 F32 DK09732-01 and 1 K08 DK 02667-01 (to K. K.) and DK 49629 (to R. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Contributed equally to the results of this article.

** To whom correspondence should be addressed: 705A Stellar-Chance, 422 Curie Blvd., Dept. of Genetics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Tel.: 215-898-9131; Fax: 215-573-2195; E-mail:taubra@mail.med.upenn.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2001 by the American Society for Biochemistry and Molecular Biology.