Effects of S/B Remedy Containing Scutellaria baicalensis and Bupleurum scorzonerifolfium on Hepatic Interleukin-6 Related Signal Transducer and Activator of Transcription 3 Activation in Mice through Cell-Cell Interaction

Abstract

It is well known that cytokines such as tumor necrosis factor-a (TNF-a) and interleukin 6 (IL-6), secreted from nonparenchymal cells, are major factors in priming quiescent hepatocytes to proliferative status during liver regeneration. 1,2) Signal transducer and activator of transcription-3 (STAT3) is a component of the transcription factor family that mediates IL-6-related growth responses. 3,4) There is evidence that the cyclin D1 gene is an important target of STAT3 in hepatocytes, and that STAT3 acts as a negative regulator of cyclin D1 transcription during fetal liver development. Whereas STAT3 positively regulates cyclin D1 expression in HCC cells at the initiation of liver regeneration.5,6) Nevertheless, information concerning how medicinal herbs affect an IL-6-STAT3 signaling pathway remains to be elucidated.The liver is an organ containing many cell types that perform different biological functions. Some liver functions are mainly achieved by one cell type, while other functions require aids from more than one cell type. For example, transforming growth factor b (TGF-b) secreted from activated Kupffer cells and hepatic stellate cells exerts potent fibrogenic effects via both autocrine and paracrine patterns in liver fibrosis. [7][8][9] During liver regeneration, lipopolysaccharide-induced TNF-a and IL-6 secreted from Kupffer cells play important roles in priming the hepatocytes, activating STAT3 signaling pathway, and finally stimulating growth of parenchymal cells or hepatocytes.1,2) Such non-parenchymal cell-hepatocyte interaction oftentimes cannot be elucidated by using a single cell system, such as Kupffer cell or hepatocyte alone cultures.Historically, herbs are used to treat many kinds of liver disease in Asia, especially in Chinese populations. Since the 1990s the prevalence and costs of alternative medicine worldwide have been increasing. 10,11) Herbal medicine or supplement use is becoming popular among patients with liver diseases. 12) However, exact cellular mechanisms on how medicinal herbs work are yet to be understood. Previously, our laboratory demonstrated that a remedy containing Scutellaria baicalensis and Bupleurum scorzonerifolfium (S/B remedy) stimulated hepatic cell growth during liver regeneration.13) Nevertheless, how S/B remedy modulates hepatic growth-related signaling pathways remains unclear. Therefore, the aim of this study was to test the hypothesis that S/B remedy induced hepatic STAT3 activation in mice through non-parenchymal cell-hepatocyte interaction. MATERIALS AND METHODSAnimals/Cell Cultures C57BL/6J, 6 to 8 weeks old, weighting 20 to 25 g, were purchased from the animal center of the National Science Council, Taiwan, R.O.C. They were fed with standard diet and water ad libitum and treated under the regulations of the "Guide for the Care and Use of Laboratory Animals" (National Academy Press; 1996). The studies were approved by the ethics committee for animal study of National Yang-Ming University, Taipei, Taiwan, R.O.C. Gadolinium chloride III (GdCl 3 , Sigma-Aldri...