Transforming growth factor b1 (TGF-b1) is reported such as ischemia and hepatotoxins. Apoptosis is usuto play an important role in the induction of liver cell ally induced by receptor-mediated processes and is unapoptosis. In this report, we demonstrate that TGF-b1 der the control of growth-regulatory signals such as induces apoptosis in a rat Morris hepatoma McA-RH8994 hormones, cytokines, and growth factors. 3,4 Although cell line and rat primary cultured hepatocytes at similar apoptosis is originally recognized as physiological cell doses and in a similar manner. Using McA-RH8994 cells, death, recent studies indicate that apoptotic cell death we screened a number of chemical reagents, aqueous is also involved in pathological cell death observed in extracts of crude drugs, and herbal medicines for their viral hepatitis and fulminant hepatitis. 2 inhibitory activities on TGF-b1-induced apoptosis. The Transforming growth factor b1 (TGF-b1) has been results indicate that Artemisiae capillaris spica (ACS)
recognized as an important cytokine in the pathogeneand the ACS-containing herbal medicine Inchin-ko-to, which are used for treatment of various liver disorders, sis of liver fibrosis, and its augmented expression was exhibited the most potent anti-apoptotic activity. Variproved in various liver disorders, both in human disous chemicals that were reported as inhibitors of eases and in animal models. [5][6][7][8][9] Recent studies have apoptosis in other experimental systems showed no evishown that TGF-b1 induces apoptosis in liver cells in dent activity. By contrast, two of nine ACS ingredients vitro, [10][11][12][13][14][15] and the in vivo close relationship between the we tested, capillin and capillene, showed activity at conhepatocytes undergoing apoptosis and the presence of centrations of submicrogram per milliliter. The inhibi-TGF-b1 protein in such cells have been reported. 16 The tory effects of Inchin-ko-to, capillin and capillene were transgenic mice overexpressing TGF-b1 selectively in also confirmed on TGF-b1-induced apoptosis of rat primary cultured hepatocytes. Inhibition of undesired the liver developed continuing apoptotic death of hepaapoptosis induced by TGF-b1 is expected to be beneficial tocytes as well as hepatic fibrosis. 17 Exogenous adminfor the treatment of various inflammatory liver diseases. istration of TGF-b1 to rodents also resulted in signifi-Our findings therefore suggest the possibility that theracant increases in hepatic cell death. 11,12,18 These results peutic effects of Inchin-ko-to on liver diseases might be strongly suggested that apoptosis induced by TGF-b1 associated with its inhibitory activity on TGF-b1-inmay be involved in various hepatic lesions. Inhibition duced liver cell apoptosis. (HEPATOLOGY 1996;23:552-559.)
of TGF-b1 effects on cell death processes is therefore expected to exhibit cytoprotective effects against liver Cell death of hepatocytes is closely associated with cell damage in hepatic diseases. pathogenesis of many kinds of liver disorders and dete-From this standpoint, we tried to develop in vitro rioration of liver functions. 1,2 It is therefore reasonable experimental systems for TGF-b1-induced liver cell to presume that drugs that are able to modulate the apoptosis. We have previously shown that TGF-b1 incell death processes in liver cells are expected to have duces apoptosis in McA-RH7777 rat hepatoma cells 14,19 therapeutic value against liver disorders caused by varand have extended our study on TGF-b1-induced cell ious pathological injuries. Liver cell death may occur death to normal hepatocytes and another Morris hepaby two different mechanisms, necrosis and apoptosis. 2 toma cell line, McA-RH8994, 20 which exhibits more dif-Liver cell necrosis results from severe cellular damage ferentiated phenotypes of liver cells. TGF-b1 was shown to induce apoptosis in both McA-RH8994 and normal hepatocytes in a similar manner. We have used Abbreviations: TGF-b1, transforming growth factor b1; ACS, Artemisiae this in vitro model to investigate various herbal medicapillaris spica; MTT, 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide.
cines for their inhibitory activities on liver cell
From the