Antiviral cytokines induce hepatic expression of the granzyme B inhibitors, proteinase inhibitor 9 and serine proteinase inhibitor 6

MB Barrie, HW Stout, MS Abougergi… - The Journal of …, 2004 - journals.aai.org
MB Barrie, HW Stout, MS Abougergi, BC Miller, DL Thiele
The Journal of Immunology, 2004journals.aai.org
Expression of the granzyme B inhibitors, human proteinase inhibitor 9 (PI-9), or the murine
orthologue, serine proteinase inhibitor 6 (SPI-6), confers resistance to CTL or NK killing by
perforin-and granzyme-dependent effector mechanisms. In light of prior studies indicating
that virally infected hepatocytes are selectively resistant to this CTL effector mechanism, the
present studies investigated PI-9 and SPI-6 expression in hepatocytes and hepatoma cells
in response to adenoviral infection and to cytokines produced during antiviral immune …
Abstract
Expression of the granzyme B inhibitors, human proteinase inhibitor 9 (PI-9), or the murine orthologue, serine proteinase inhibitor 6 (SPI-6), confers resistance to CTL or NK killing by perforin-and granzyme-dependent effector mechanisms. In light of prior studies indicating that virally infected hepatocytes are selectively resistant to this CTL effector mechanism, the present studies investigated PI-9 and SPI-6 expression in hepatocytes and hepatoma cells in response to adenoviral infection and to cytokines produced during antiviral immune responses. Neither PI-9 nor SPI-6 expression was detected by immunoblotting in uninfected murine or human hepatocytes. Similarly, human Huh-7 hepatoma cells were found to express only very low levels of PI-9 relative to levels detected in perforin-and granzyme-resistant CTL or lymphokine-activated killer cells. Following in vivo adenoviral infection or in vitro culture with IFN-αβ or IFN-γ, SPI-6 expression was induced in murine hepatocytes. Similarly, after culture with IFN-α, induction of PI-9 mRNA and protein expression was observed in human hepatocytes and Huh-7 cells. IFN-γ and TNF-α also induced 4-to 10-fold higher levels of PI-9 mRNA expression in Huh-7 cells, whereas levels of mRNA encoding a related serine proteinase inhibitor, proteinase inhibitor 8, were unaffected by culture of Huh-7 cells with IFN-α, IFN-γ, or TNF-α. These findings indicate that cytokines that promote antiviral cytopathic responses also regulate expression of the cytoprotective molecules, PI-9 and SPI-6, in hepatocytes that are potential targets of CTL and NK effector mechanisms.
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