Antiviral Cytokines Induce Hepatic Expression of the Granzyme B Inhibitors, Proteinase Inhibitor 9 and Serine Proteinase Inhibitor 6

• Published in: The Journal of immunology (1950) Vol. 172; no. 10; pp. 6453 - 6459
• Main Authors: Barrie, Mahmoud B, Stout, Heather W, Abougergi, Marwan S, Miller, Bonnie C, Thiele, Dwain L
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.05.2004
• Subjects: Adenoviridae Infections - enzymology; Adenoviridae Infections - immunology; Animals; Antiviral Agents - pharmacology; Carcinoma, Hepatocellular - enzymology; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - virology; Cell Line, Tumor; Cells, Cultured; Cytokines - pharmacology; Cytotoxicity Tests, Immunologic; Granzymes; Hepatocytes - enzymology; Hepatocytes - immunology; Hepatocytes - virology; Humans; Immunity, Innate; Membrane Glycoproteins - physiology; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Mice, Knockout; Perforin; Pore Forming Cytotoxic Proteins; Serine Endopeptidases - biosynthesis; Serine Endopeptidases - metabolism; Serine Endopeptidases - physiology; Serpins - biosynthesis; T-Lymphocytes, Cytotoxic - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.172.10.6453

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-alphabeta or IFN-gamma, SPI-6 expression was induced in murine hepatocytes. Similarly, after culture with IFN-alpha, induction of PI-9 mRNA and protein expression was observed in human hepatocytes and Huh-7 cells. IFN-gamma and TNF-alpha 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-alpha, IFN-gamma, or TNF-alpha. 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.