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Vol. 54, Issue 2, 313-321, August 1998
and Apoptosis
Laboratory of Metabolism (H.Z., P.M.F.-S., F.J.G.),
Laboratory of
Molecular Pharmacology (M.S.S., A.J.F.), and
Laboratory of
Chemoprevention (J.L., A.B.R.), National Cancer Institute, National
Institutes of Health, Bethesda, Maryland 20892
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-
(TGF) 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
TGF expression and apoptosis in this mouse line was analyzed. Livers
from Ahr/ mice had marked increase in active
TGF1 and TGF3 proteins and elevated numbers of hepatocytes
undergoing apoptosis compared with wild-type mice. Furthermore,
increases in TGF 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 TGF 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 TGF and altered cell cycle control.
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