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Science 22 November 1996:
Vol. 274. no. 5291, pp. 1379 - 1383
DOI: 10.1126/science.274.5291.1379
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Reports

Liver Failure and Defective Hepatocyte Regeneration in Interleukin-6-Deficient Mice

Drew E. Cressman, * Linda E. Greenbaum, Robert A. DeAngelis, Gennaro Ciliberto, Emma E. Furth, Valeria Poli, Rebecca Taub dagger

Liver regeneration stimulated by a loss of liver mass leads to hepatocyte and nonparenchymal cell proliferation and rapid restoration of liver parenchyma. Mice with targeted disruption of the interleukin-6 (IL-6) gene had impaired liver regeneration characterized by liver necrosis and failure. There was a blunted DNA synthetic response in hepatocytes of these mice but not in nonparenchymal liver cells. Furthermore, there were discrete G1 phase (prereplicative stage in the cell cycle) abnormalities including absence of STAT3 (signal transducer and activator of transcription protein 3) activation and depressed AP-1, Myc, and cyclin D1 expression. Treatment of IL-6-deficient mice with a single preoperative dose of IL-6 returned STAT3 binding, gene expression, and hepatocyte proliferation to near normal and prevented liver damage, establishing that IL-6 is a critical component of the regenerative response.

D. E. Cressman, L. E. Greenbaum, R. A. DeAngelis, R. Taub, Department of Genetics and Medicine, University of Pennsylvania School of Medicine, 705a Stellar-Chance, 422 Curie Boulevard, Philadelphia, PA 19104-6145, USA.
G. Ciliberto and V. Poli, Instituto di Ricerche di Biologia Molecolare, IRBM Pietro Angeletti, Via Pontina Km 30.600, Pomezia (Roma), Italy.
E. E. Furth, Department of Pathology, University of Pennsylvania School of Medicine, 705a Stellar-Chance, 422 Curie Boulevard, Philadelphia, PA 19104-6145, USA.
*   Present address: Duke University Medical Center, Research Drive, Durham, NC 27710, USA.

dagger    To whom correspondence should be addressed.

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M. Macias-Silva, W. Li, J. I. Leu, M. A. S. Crissey, and R. Taub (2002)
J. Biol. Chem. 277, 28483-28490
   Abstract »    Full Text »    PDF »
4-Hydroxynonenal Decreases Interleukin-6 Expression and Protein Production in Primary Rat Kupffer Cells by Inhibiting Nuclear Factor-kappa B Activation.
S. W. Luckey, M. Taylor, B. P. Sampey, R. I. Scheinman, and D. R. Petersen (2002)
J. Pharmacol. Exp. Ther. 302, 296-303
   Abstract »    Full Text »    PDF »
STAT-3 Overexpression and p21 Up-Regulation Accompany Impaired Regeneration of Fatty Livers.
M. Torbenson, S. Q. Yang, H. Z. Liu, J. Huang, W. Gage, and A. M. Diehl (2002)
Am. J. Pathol. 161, 155-161
   Abstract »    Full Text »    PDF »
Pro-inflammatory Cytokines Tumor Necrosis Factor alpha and Interleukin-6 and Survival Factor Epidermal Growth Factor Positively Regulate the Murine GSTA4 Enzyme in Hepatocytes.
F. Desmots, M. Rissel, D. Gilot, D. Lagadic-Gossmann, F. Morel, C. Guguen-Guillouzo, A. Guillouzo, and P. Loyer (2002)
J. Biol. Chem. 277, 17892-17900
   Abstract »    Full Text »    PDF »
Interaction between STAT-3 and HNF-3 Leads to the Activation of Liver-Specific Hepatitis B Virus Enhancer 1 Function.
G. Waris and A. Siddiqui (2002)
J. Virol. 76, 2721-2729
   Abstract »    Full Text »    PDF »
Cardiac-specific Activation of Signal Transducer and Activator of Transcription 3 Promotes Vascular Formation in the Heart.
T. Osugi, Y. Oshima, Y. Fujio, M. Funamoto, A. Yamashita, S. Negoro, K. Kunisada, M. Izumi, Y. Nakaoka, H. Hirota, et al. (2002)
J. Biol. Chem. 277, 6676-6681
   Abstract »    Full Text »    PDF »
Stabilization of Tumor Necrosis Factor alpha mRNA by Chronic Ethanol. ROLE OF A + U-RICH ELEMENTS AND p38 MITOGEN-ACTIVATED PROTEIN KINASE SIGNALING PATHWAY.
R. Kishore, M. R. McMullen, and L. E. Nagy (2001)
J. Biol. Chem. 276, 41930-41937
   Abstract »    Full Text »    PDF »
Reduced body fat and increased hepatic lipid synthesis in mice bearing interleukin-6-secreting tumor.
S. Metzger, T. Hassin, V. Barash, O. Pappo, and T. Chajek-Shaul (2001)
Am J Physiol Endocrinol Metab 281, E957-E965
   Abstract »    Full Text »    PDF »
A tumor necrosis factor alpha - and interleukin 6-inducible protein that interacts with the small subunit of DNA polymerase delta and proliferating cell nuclear antigen.
H. He, C.-K. Tan, K. M. Downey, and A. G. So (2001)
PNAS 98, 11979-11984
   Abstract »    Full Text »    PDF »
Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver.
X. Wang, E. Quail, N.-J. Hung, Y. Tan, H. Ye, and R. H. Costa (2001)
PNAS 98, 11468-11473
   Abstract »    Full Text »    PDF »
Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration.
D. A. Rudnick, D. H. Perlmutter, and L. J. Muglia (2001)
PNAS
   Abstract »    Full Text »    PDF »
Retarded Liver Growth in Interleukin-6-Deficient and Tumor Necrosis Factor Receptor-1-Deficient Mice.
V. Wallenius, K. Wallenius, M. Hisaoka, J. Sandstedt, C. Ohlsson, M. Kopf, and J.-O. Jansson (2001)
Endocrinology 142, 2953-2960
   Abstract »    Full Text »    PDF »
Hepatic Hyperplasia in Noncirrhotic Fatty Livers: Is Obesity-related Hepatic Steatosis a Premalignant Condition?.
S. Yang, H. Z. Lin, J. Hwang, V. P. Chacko, and A. M. Diehl (2001)
Cancer Res. 61, 5016-5023
   Abstract »    Full Text »    PDF »
Differential Effects of Transforming Growth Factor-{beta}1, a Fibrogenic Factor, on Macrophage-Like Cells (HS-P) and Myofibroblastic Cells (MT-9) In Vitro.
J. Yamate, M. Maeda, S. J. Benn, J. E. Laithwaite, A. Allan, M. Ide, M. Kuwamura, T. Kotani, S. Sakuma, and J. Lamarre (2001)
Toxicol Pathol 29, 483-491
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Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats.
Y. G. Weiss, L. Bellin, P. K. Kim, K. M. Andrejko, C. A. Haaxma, N. Raj, E. E. Furth, and C. S. Deutschman (2001)
Am J Physiol Gastrointest Liver Physiol 280, G968-G973
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Cyclin D1 is an early target in hepatocyte proliferation induced by thyroid hormone (T3).
M. PIBIRI, G. M. LEDDA-COLUMBANO, C. COSSU, G. SIMBULA, M. MENEGAZZI, H. SHINOZUKA, and A. COLUMBANO (2001)
FASEB J 15, 1006-1013
   Abstract »    Full Text »    PDF »
Effects of Preoperative Steroid Administration on Surgical Stress in Hepatic Resection: Prospective Randomized Trial.
Y.-i. Yamashita, M. Shimada, T. Hamatsu, T. Rikimaru, S. Tanaka, K. Shirabe, and K. Sugimachi (2001)
Arch Surg 136, 328-333
   Abstract »    Full Text »    PDF »
Plasminogen Activators Direct Reorganization of the Liver Lobule after Acute Injury.
J. A. Bezerra, A. R. Currier, H. Melin-Aldana, G. Sabla, T. H. Bugge, K. W. Kombrinck, and J. L. Degen (2001)
Am. J. Pathol. 158, 921-929
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A Novel Role of Complement: Mice Deficient in the Fifth Component of Complement (C5) Exhibit Impaired Liver Regeneration.
D. Mastellos, J. C. Papadimitriou, S. Franchini, P. A. Tsonis, and J. D. Lambris (2001)
J. Immunol. 166, 2479-2486
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Impaired Preneoplastic Changes and Liver Tumor Formation in Tumor Necrosis Factor Receptor Type 1 Knockout Mice.
B. Knight, G. C.T. Yeoh, K. L. Husk, T. Ly, L. J. Abraham, C. Yu, J. A. Rhim, and N. Fausto (2000)
J. Exp. Med. 192, 1809-1818
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Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice.
R. M. GALLUCCI, P. P. SIMEONOVA, J. M. MATHESON, C. KOMMINENI, J. L. GURIEL, T. SUGAWARA, and M. I. LUSTER (2000)
FASEB J 14, 2525-2531
   Abstract »    Full Text »


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