The Involvement of Aryl Hydrocarbon Receptor in the Activation of Transforming Growth Factor-β and Apoptosis
- 1 August 1998
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET)
- Vol. 54 (2), 313-321
- https://doi.org/10.1124/mol.54.2.313
Abstract
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-β (TGFβ) 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 TGFβ expression and apoptosis in this mouse line was analyzed. Livers from Ahr−/− mice had marked increase in active TGFβ1 and TGFβ3 proteins and elevated numbers of hepatocytes undergoing apoptosis compared with wild-type mice. Furthermore, increases in TGFβ and apoptotic cells were found in the portal areas of the liver, where fibrosis is found in theAhr−/− 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 TGFβ 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 fromAhr−/− hepatocytes stimulated apoptosis in cultured hepatocytes from wild-type mice. Taken together, these findings suggest that the phenotypic abnormalities inAhr−/− mice could be mediated in part by abnormal levels of active TGFβ and altered cell cycle control.Keywords
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