Autocrine expression of activated transforming growth factor-β1 induces apoptosis in normal rat liver

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>(*) over bar * (L)], or activated TGF-beta (1) [TGF-beta>(*) over bar * (A)]. Additional animals underwent two-thirds partial hepatectomy (PH) 24 h after injection. Increased hepatocyte apoptosis was observed in TGF-beta>(*) over bar * (A)-injected but not TGF-beta>(*) over bar * (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>(*) over bar * (A)-injected animals 48 h after injection. Furthermore, TGF-beta>(*) over bar * (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>(*) over bar * (A)-injected rats, respectively. TGF-beta>(*) over bar * (A)-induced apoptosis in primary rat hepatocytes was blocked with a pancaspase inhibitor. Thus autocrine expression of TGF-beta>(*) over bar * (A) but not TGF-beta>(*) over bar * (L) induces hepatocyte apoptosis in the normal rat liver. Rats overexpressing TGF-beta>(*) over bar * (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.