Zaher H, Fernandez-Salguero P M, Letterio J, Sheikh M S, Fornace A J, Roberts A B, Gonzalez F J
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Mol Pharmacol. 1998 Aug;54(2):313-21. doi: 10.1124/mol.54.2.313.
The aryl hydrocarbon receptor (AHR) is believed to mediate many of the toxic, carcinogenic, and teratogenic effects of environmental contaminants such as dioxins, polycyclic aromatic hydrocarbons, and polyhalogenated biphenyls. Ligands for the AHR have been shown to influence cell proliferation, differentiation, and apoptosis, but the mechanism by which the AHR affects the cell cycle is not known. Increased levels of mature transforming growth factor-beta (TGFbeta) has been correlated with reduced cell proliferation and increased rates of apoptosis and fibrosis. Based on the increase in portal fibrosis and small liver size observed in AHR-null (Ahr-/-) mice, the relationship between TGFbeta expression and apoptosis in this mouse line was analyzed. Livers from Ahr-/- mice had marked increase in active TGFbeta1 and TGFbeta3 proteins and elevated numbers of hepatocytes undergoing apoptosis compared with wild-type mice. Furthermore, increases in TGFbeta and apoptotic cells were found in the portal areas of the liver, where fibrosis is found in the Ahr-/- mice. In vitro, primary hepatocyte cultures from Ahr-/- mice exhibited a high number of cells in later stages of apoptosis and an elevated secretion of active TGFbeta into the media compared with cultures from wild-type mice, which have previously been shown to secrete only latent forms of the molecule. Conditioned media from Ahr-/- hepatocytes stimulated apoptosis in cultured hepatocytes from wild-type mice. Taken together, these findings suggest that the phenotypic abnormalities in Ahr-/- mice could be mediated in part by abnormal levels of active TGFbeta and altered cell cycle control.
芳烃受体（AHR）被认为介导了二恶英、多环芳烃和多卤联苯等环境污染物的许多毒性、致癌性和致畸性作用。已证明AHR的配体可影响细胞增殖、分化和凋亡，但AHR影响细胞周期的机制尚不清楚。成熟转化生长因子-β（TGFβ）水平的升高与细胞增殖减少、凋亡率和纤维化增加相关。基于在AHR基因敲除（Ahr-/-）小鼠中观察到的门脉纤维化增加和肝脏体积减小，分析了该小鼠品系中TGFβ表达与凋亡之间的关系。与野生型小鼠相比，Ahr-/-小鼠的肝脏中活性TGFβ1和TGFβ3蛋白显著增加，发生凋亡的肝细胞数量增多。此外，在Ahr-/-小鼠出现纤维化的肝脏门脉区域发现了TGFβ和凋亡细胞的增加。在体外，与野生型小鼠的肝细胞培养物相比，Ahr-/-小鼠的原代肝细胞培养物在凋亡后期有大量细胞，且向培养基中分泌的活性TGFβ增加，野生型小鼠的肝细胞培养物此前已证明仅分泌该分子的潜伏形式。Ahr-/-肝细胞的条件培养基可刺激野生型小鼠培养的肝细胞发生凋亡。综上所述，这些发现表明，Ahr-/-小鼠的表型异常可能部分由活性TGFβ水平异常和细胞周期控制改变介导。
