MODULATION OF PERFORIN AND GRANZYME MESSENGER-RNA EXPRESSION IN HUMANNATURAL-KILLER-CELLS

Perforin and granzymes are proteins thought to play a relevant role in cell-mediated cytotoxicity. These molecules are constitutively expres sed in NK cells and their level of expression in cytotoxic T lymphocyt es is regulated by several cytokines. We analyzed the mechanisms by wh ich cytokines and cellular ligands known to modulate NK cell-mediated cytotoxicity affect the expression of the mRNA encoding granzyme A and B and perforin in NK cells. Our data indicate that IL-2 and IL-12 ind uce increased accumulation of both perforin and, to a higher degree, g ranzyme B mRNA. In contrast, binding of target cells or immune complex es up-regulates expression of granzyme B mRNA without altering that of perforin. Results of in situ hybridization experiments confirm that m RNA for both molecules are expressed at low levels in most NK cells, a nd that both are induced to accumulate by the two cytokines in the maj ority of the cells. The mechanisms by which IL-2 and IL-12 regulate ex pression of the two molecules are, in part, distinct: both cytokines i ncrease the transcriptional rate of the encoding genes, whereas only I L-2 acts also at a post-transcriptional level to increase the stabilit y of their mRNA.