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[proteinase inhibitor-9] the approved gene symbol for this enzyme is Serpin B9. The protein has been referred to also as CAP3 [cytoplasmic antiproteinase 3]. The murine ortholog has been identified as serine protease inhibitor-6 (SPI-6) (Sun et al, 1996, 1997). The human cDNA has been cloned by Sprecher et al (1995). The sequence of PI9 is closely related to PI6 and the viral serpin crmA (Sprecher et al, 1995; Sun et al, 1996).

This protein (374 amino acids; Sprecher et al, 1995) is a member of a large class of serine proteinase inhibitors (serpins), which inactivate serine proteinases. PI9 is a cytosolic protein that is not secreted (Sun et al, 1996). It does not inhibit trypsin, papain, thrombin, or Staphylococcus aureus endoproteinase Glu-C (Sprecher et al, 1995) and has been shown to bind to and inhibit granzyme B (Sun et al, 1996). Dahlen et al (1997) have reported that PI9 inhibits the bacterial endoproteinase subtilisin A. Dahlen et al (1999) have reported that PI9 inhibits human neutrophil elastase. Annand et al (1999) and Krieg et al (2001) have identified PI9 as an endogenous inhibitor of caspase-1. To a smaller extent PI9 also inhibits caspase-4 and caspase-8, but not caspase-3 (Annand et al, 1999). Young et al (2000) have reported that PI9 accounts for the endogenous caspase-1 inhibitory activity in human smooth muscle cells and prevents processing of the natural substrates of the enzyme, IL1-beta and IL18 precursors. Mahrus et al (2004) have reported that granzyme M effectively hydrolyzes and inactivates PI9, which, therefore, may participate also in various cell death processes or the avoidance of cell death.

Sun et al (1996) have reported expression of PI9 in lymphocytes, natural killer cell leukemia cell lines, and peripheral blood mononuclear cells. Classen et al (2006) have reported expression of PI9 in monocytes. Up-regulation of PI9 expression can be observed in lymphocytes and monocytes of patients with acute EBV infection, but not in response to bacterial infection. Horie et al (2005) have reported strong expression of PI9 in an NK-cell line (YT-N10), and expression to a lesser extent in a B-acute lymphoblastic leukemia cell line (U-Tree02), EBV-transformed B-cells, a CD8(+) T-cell clone, and a cell line derived from megakaryocytes. Bladergroen et al (2005) have reported expression of PI9 by human mast cells. They have suggested that this may protect mast cells against apoptosis induced by granzyme B released during the initiation of the local inflammatory responses.

Bladergroen et al (2001) have demonstrated expression in dendritic cells, but not macrophage populations, B-cells, T-cells, and endothelial cells. The authors have observed high levels of PI9 expression in immunologically privileged sites (eye lens, testis, ovary, placenta) and have suggested that PI9 expression may be important for resistance to cell death by apoptosis induced by granzyme B. Kannan-Thulasiraman and Shapiro (2002) have reported that IL1-beta strongly induces expression of PI9 in hepatoma cells, suggesting a negative feedback mechanism controlling the anti-inflammatory and anti-apoptotic activities of PI9. Vermijlen et al (2002) have reported PI9 expression in hepatic NK-cells and sinusoidal endothelial cells. Hepatic NK-cells kill splenic/blood NK-cell resistant and FAS ligand sensitive tumor cells exclusively by the perforin / granzyme pathway. PI9 expression in liver sinusoidal endothelial cells may protect the liver microenvironment from this highly active pathway used to kill metastasizing cancer cells.

Buzza et al (2006) have shown that PI9 is expressed highly by the extravillous trophoblasts that have invaded the decidua, and this high expression is maintained throughout pregnancy. Similar levels are found in proliferative villous cytotrophoblasts but not in syncytial trophoblasts except in the last few weeks of pregnancy. Choriocarcinoma cell lines also express very high levels of PI9, which may provide protection from apoptosis mediated by granzyme B.

The expression of PI9 is induced strongly in hepatocytes in response to treatment with estrogen (Krieg et al, 2001; Kanamori et al, 2000). Jiang et al (2006) have reported that estrogen induction of PI9 protects hepatocytes against apoptosis dependent on granzyme B and mediated by cytotoxic T-cells or NK-cells. Knock-down of PI9 expression blocks the protective effect of estrogen. The authors have suggested that estrogen induction of PI9 may impair immune surveillance, for example by NK-cells (Jiang et al, 2007). This would be aimed at the destruction of newly transformed cells, and possibly provides a mechanism explaining an estrogen-mediated increase in tumor incidence as reflected also in an increased risk of developing breast, cervical, and liver cancer after exposure to estrogens. Stout-Delgado (2007) have reported that the regulated expression of PI9 in hepatocytes during viral infection or following non-infectious causes of liver injury protects hepatocytes against excessively vigorous granzyme B dependent killing but may also delay immune clearance of virally infected hepatocytes. Stout-Delgado et al (2007) have shown that PI9 expression is up-regulated selectively in hepatocytes in response to infiltration of the liver by NK-cells that express perforin and enzymatically active granzyme B.

Buzza et al (2001) have reported expression of PI9 in endothelial cells and mesothelial cells. Hirst et al (2001) have reported that PI9 is expressed abundantly in human testicular Sertoli cells and placental syncytial trophoblasts. van Houdt et al (2005) have reported expression of PI9 in melanoma cells. Expression of PI-9 in metastatic melanoma cells is associated with unfavorable clinical outcome.

Rowshani et al (2005) have reported that soluble PI9 may have extracellular functions. PI9 circulates in blood complexed with granzyme B. Levels increase on primary CMV infection and are significantly higher in symptomatic than in asymptomatic patients. Levels do not change in response to subclinical or acute rejection after renal transplantation.
Phillips et al (2004) have reported a role of PI9 in CD8(+) memory cell homeostasis and proposed that PI9 functions as a protective molecule that may shield metabolically active CD8(+) memory T-cells from their own effector molecules. Watchmaker et al (2008) have reported that memory CD8(+) T-cells that release TNF-alpha before the release of cytotoxic granules induce dendritic cell expression of PI9 and protect dendritic cells from killing by cytotoxic T-cells with similar efficacy as CD4(+) Th cells.

Zhang et al (2006) have shown that by inhibiting granzyme B PI9 protects cytotoxic T-cells from self-inflicted injury. Infection with either Lymphocytic Choriomeningitis virus (LCMV) or Listeria monocytogenes (LM) reveals increased apoptosis and diminished survival of PI9 knock-out cytotoxic T-cells, which is cell autonomous and can be corrected by granzyme B deficiency. PI9 knock-out mice are impaired in their ability to clear LCMV infection.

Kummer et al (2007) have shown that PI9 inhibits apoptosis elicited by TNF-alpha, TRAIL, and FAS ligand in certain cell lines sensitive to TNF-alpha by directly interacting with the intermediate active forms of caspase-8 and caspase-10. A major determinant of cell death in NK-cells, termed granzyme B leakage-induced cell death, is an excess of leaked granzyme B over its inhibitor (Ida et al, 2003). Bots et al (2007) have shown that PI9 expression protects murine dendritic cells against apoptosis mediated by cytotoxic T-cells.

Virally infected hepatocytes have been shown to resist killing by cytotoxic T-cells or by NK-cells, mediated by perforin and granzymes by expressing PI9 (Barrie et al, 2004). Barrie et al (2004) have reported that cytokines promoting antiviral cytopathic responses also regulate expression of cytoprotective Uninfected hepatocytes do not express PI9 or SPI-6, the murine ortholog. Also, hepatocellular carcinoma cells express only low levels of PI9. Infection with adenoviruses in vivo or exposure of cells to IFN-alpha, IFN-beta, or IFN-gamma induces PI9 expression in murine hepatocytes. In human hepatoma cells PI9 expression becomes upregulated in response to IFN-alpha, IFN-gamma, and TNF-alpha.

Medema et al (2001) have reported that the blockade of the granzyme B / perforin pathway through overexpression of PI9 constitutes a mechanism for immune escape by tumors. Expression of PI9 in a variety of human and murine tumors results in the resistance of tumor cells to killing mediated by cytotoxic T-cells both in vitro and in vivo. Bird et al (1998) have suggested that PI9 protects cytotoxic T-cells and perhaps bystander cells against premature death triggered by miscompartmentalized or misdirected granzyme B, but does not interfere with the deletion of cells from the immune system via the FAS pathway of cell death. Bladergroen et al (2002) have reported expression of PI9 in tumor cells in patients with non-Hodgkin and Hodgkin lymphoma and suggested that this may be a protective mechanism for tumor cells to circumvent killing by cytotoxic T-cells.

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