Interferon α-induced apoptosis on rat preneoplastic liver is mediated by hepatocytic transforming growth factor β1

被引:20
作者
Alvarez, MD
Ronco, MT
Ochoa, JE
Monti, JA
Carnovale, CE
Pisani, GB
Lugano, MC
Carrillo, MC
机构
[1] Univ Nacl Rosario, Fac Ciencias Bioquim & Farmaceut, Inst Fisiol Expt IFISE, Area Morfol, RA-2000 Rosario, Santa Fe, Argentina
[2] Consejo Nacl Invest Cient & Tecn, Inst Fisiol Expt, RA-1033 Buenos Aires, DF, Argentina
关键词
D O I
10.1002/hep.20307
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
In previous work we showed that interferon alfa-2b (IFN-alpha2b) increases apoptosis on rat hepatic preneoplastic foci. The aim of this study was to determine if transforming growth factor beta(1) (TGF-beta(1)) was involved in the programmed cell death on the foci. Animals were divided into 6 groups: subjected to a 2-phase model (diethylnitrosamine plus 2-acetylaminofluorene) of preneoplasia development (group 1); treated with IFN-alpha2b during the 2 phases (group 2); treated with IFN-alpha2b during initiation with diethylnitrosamine (group 3); treated with IFN-alpha2b during 2-acetylaminofluorene administration (group 4); subjected only to an initiation stage (group 5); and treated with IFN-alpha2b during the initiation period (group 6). Serum TGF-beta(1) levels were increased in IFN-alpha2b-treated rats. Immunohistochemical studies showed that IFN-alpha2b significantly increased the quantity of TGF-beta(1)-positive hepatocytes; in groups 2 to 4. Phosphorylated-Smads-2/3 (p-Smads-2/3) proteins in liver nuclear extracts were significantly elevated. To determine the source of TGF-beta(1), isolated hepatocytes, Kupffer cells, and peritoneal macrophages from animals in groups I and 5 were cultured with or without IFN-alpha2b. IFN-alpha2b stimulus induced several-fold increases of TGF-beta(1) secretion from hepatocytes. Neither Kupffer cells nor peritoneal macrophages secreted detectable TGF-beta(1) levels when they were treated with IFN-alpha2b. IFN-alpha2b-stimulated cultured hepatocytes from preneoplastic livers showed enhanced apoptosis, measured by fluorescence microscopy and caspase-3 activity. They presented higher nuclear accumulation of p-Smads-2/3, indicating increased TGF-beta(1) signaling. When anti-TGF-beta(1), was added to the culture media, TGF-beta(1) activation and apoptosis induced by IFN-alpha2b were blocked. In conclusion, IFN-alpha2b-induced production of TGF-beta(1) by hepatocytes from preneoplastic liver is involved in the apoptotic elimination of altered hepatic foci.
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页码:394 / 402
页数:9
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