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Am J Physiol Gastrointest Liver Physiol 280: G139-G148, 2001;
0193-1857/01 $5.00
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Vol. 280, Issue 1, G139-G148, January 2001

Autocrine expression of activated transforming growth factor-beta 1 induces apoptosis in normal rat liver

Laura W. Schrum1, Mark A. Bird1, Olga Salcher2, Elmar-Reinhold Burchardt2, Joe W. Grisham3, David A. Brenner4,5, Richard A. Rippe4, and Kevin E. Behrns1

Departments of 1 Surgery, 4 Medicine, 5 Biochemistry and Biophysics, and 3 Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7210; and 2 Bayer Pharmaceuticals, Wupertal 20000, Germany

The aim of this study was to determine the differential effects of latent and activated transforming growth factor (TGF)-beta 1 in growth control of normal and proliferating hepatocytes in vivo. Rats were injected with adenoviruses expressing control transgenes (Ctrl), latent TGF-beta 1 [TGF-beta (L)], or activated TGF-beta 1 [TGF-beta (A)]. Additional animals underwent two-thirds partial hepatectomy (PH) 24 h after injection. Increased hepatocyte apoptosis was observed in TGF-beta (A)-injected but not TGF-beta (L)-injected animals 24 h postinjection (10.5%) compared with Ctrl animals (0.37%). The percent of apoptotic cells increased to 32.1% in TGF-beta (A)-injected animals 48 h after injection. Furthermore, TGF-beta (A)-injected rats did not survive 24 h after PH. Four hours after PH, 0.25 and 14.1% apoptotic hepatocytes were seen in Ctrl- and TGF-beta (A)-injected rats, respectively. TGF-beta (A)-induced apoptosis in primary rat hepatocytes was blocked with a pancaspase inhibitor. Thus autocrine expression of TGF-beta (A) but not TGF-beta (L) induces hepatocyte apoptosis in the normal rat liver. Rats overexpressing TGF-beta (A) do not survive two-thirds PH due to hepatic apoptosis. Thus activation of TGF-beta 1 may be a critical step in the growth control of normal and proliferating rat hepatocytes.

hepatic regeneration; caspase activity; growth factors; adenovirus; partial hepatectomy


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[Abstract] [Full Text] [PDF]


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