It is currently thought that glucocorticosteriods have a direct effect on the transcription
of the alpha, beta and gamma fibrinogen genes. However, our studies indicate that
while corticosteriods play a role in fibrinogen production, this role is not due to
transcriptional activation via glucocorticosteriod receptors. In initial experiments,
we compared the levels of fibrinogen mRNA in hepatocytes isolated from hypophysectomized
rats to those from control animals. The levels of mRNA in hypophysectomized rats,
which produce little ACTH or corticosteriods, were significantly higher than the levels
in control animals. Albumin mRNA levels were unaffected by hypophysectomy. These results
are in opposition to those which we had anticipated. Based on previously published
data, we had thought that physiologic deprivation of corticosteriods would lead to
decreased levels of fibrinogen. We propose that these results are related to the negative
feedback that corticosteroids have on Hepatocyte Stimulating Factor (HSF) production
through a tightly controlled feedback circuit. To investigate the role of corticosteriods
in fibrinogen gene regulation, we have conducted experiments with primary hepatocytes
in culture and rat FAZA cells (continuous hepatoma cell line). There is a 4 to 5 fold
increase in fibrinogen production when these cells are treated with HSF but no change
when these cells are treated with dexamethasone alone. However, there is a marked
additional increase in the production of fibrinogen with the combination of dexamethasone
and HSF. Data gathered through kinetic analysis of this synergistic interaction suggest
that the maximum response to HSF requires another gene product whose production is
responsive to dexamethasone. Detailed analysis of the rate of transcription of thegamma
fibrinogen gene, its processing and mRNA turnover suggests a specific role for this
gene product in regulating fibrinogen synthesis. Characterization of this gene product
will lead to greater understanding of the regulation of the Acute Phase Reactants.
