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This version published online on November 23, 2005
Endocrinology, doi:10.1210/en.2005-0996
A more recent version of this article appeared on March 1, 2006
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Submitted on August 4, 2005
Accepted on November 14, 2005

Estrogen Induction of the Granzyme B Inhibitor, Proteinase Inhibitor 9, Protects Cells Against Apoptosis Mediated by Cytotoxic T Lymphocytes and Natural Killer Cells

Xinguo Jiang, Brent A. Orr, David M. Kranz, and David J. Shapiro*

Department of Biochemistry, University of Illinois, Urbana, IL 61801

* To whom correspondence should be addressed. E-mail: djshapir{at}uiuc.edu.

Exposure to estrogens is associated with an increased risk of developing breast cancer, cervical cancer and liver cancer. Estrogens strongly induce the human granzyme B inhibitor, proteinase inhibitor 9 (PI-9). Since cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, use the granzyme pathway to induce apoptosis of target cells, we tested the ability of activated CTLs and the human NK cell line, YT cells, to lyse human liver cells. Estrogen induction of PI-9 protected the liver cells against CTL and NK cell-mediated, granzyme-dependent, apoptosis. RNAi knockdown of PI-9 blocked the protective effect of estrogen. This work demonstrates that estrogens can act on target cells to control their destruction by immune system cells and shows that induction of PI-9 expression can inhibit both CTL and NK cell-mediated apoptosis. Estrogen induction of PI-9 may reduce the ability of cytolytic lymphocytes-mediated immune surveillance to destroy newly transformed cells, possibly providing a novel mechanism for an estrogen-mediated increase in tumor incidence.
Key words: estrogen • proteinase inhibitor 9 • PI-9 • SerpinB9 • CTL • NK • granzyme B • apoptosis




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