Prostaglandin E2 (EP1) Receptor Agonist-Induced DNA Synthesis and Proliferation in Primary Cultures of Adult Rat Hepatocytes: The Involvement of TGF-α
We investigated the effects of prostaglandin (EP) receptor subtype agonists on DNA synthesis and proliferation in primary cultures of adult rat hepatocytes to elucidate their mechanisms of action. Maintained in short-term cultures (i.e. 3.5 h) in a serum-free, defined medium, hepatocyte parenchymal...
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Published in | Endocrinology (Philadelphia) Vol. 142; no. 10; pp. 4428 - 4440 |
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Main Authors | , , |
Format | Journal Article |
Language | English |
Published |
Endocrine Society
01.10.2001
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Online Access | Get full text |
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Summary: | We investigated the effects of prostaglandin (EP) receptor
subtype agonists on DNA synthesis and proliferation in primary cultures
of adult rat hepatocytes to elucidate their mechanisms of action.
Maintained in short-term cultures (i.e. 3.5 h) in a
serum-free, defined medium, hepatocyte parenchymal cells
underwent DNA synthesis and proliferation in the presence of
sulprostone (10−6 m), PGE2
(10−6 m), and
17-phenyl-trinor-PGE2 (10−9 m) in
a time- and dose-dependent manner. PGE2 was less potent
than 17-phenyl-trinor-PGE2 in stimulating hepatocyte
mitogenesis. Sulprostone (10−6 m) and
11-deoxy-PGE1 (10−6 m) showed weak
and insignificant stimulation, respectively, for hepatocyte
mitogenesis. These effects of PGE2,
17-phenyl-trinor-PGE2, and sulprostone were abolished
by treatment with a specific EP1 receptor antagonist,
SC-51322, or the PLC inhibitor U-73122. The effects of these
EP1 receptor agonists were potentiated by ionomycin and
blocked by verapamil. Hepatocyte mitogenesis was almost completely
blocked by specific inhibitors of growth-related signal transducers,
such as genistein, wortmannin, PD98059, and rapamycin. A monoclonal
antibody against TGF-α dose-dependently inhibited PGE2-
and 17-phenyl-trinor-PGE2-induced hepatocyte mitogenesis.
Treatment with the EP1 receptor agonists significantly
increased the secretion of TGF-α, reaching a maximum within 5 min.
The increase in TGF-α secretion was blocked by SC-51322,
U-73122, somatostatin, and verapamil and potentiated by ionomycin.
These results indicate that the proliferative mechanisms of action of
EP1 receptor agonists are mediated through an increase in
the autocrine secretion of TGF-α, which is dependent on the
EP1 receptor/G-protein involved in PLC
regulation/PLC/Ca2+ system. The locally secreted
TGF-α, in turn, acts as a complete mitogen that stimulates the
tyrosine kinase/MAPK pathway in these cells. |
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ISSN: | 0013-7227 1945-7170 |
DOI: | 10.1210/endo.142.10.8450 |