DIFFERENTIAL REGULATION OF HUMAN NK CELL-ASSOCIATED GENE-EXPRESSION FOLLOWING ACTIVATION BY IL-2, IFN-ALPHA AND PMA IONOMYCIN/

Natural killer (NK) cells are important in host-defense mechanisms aga inst infection and cancer and also participate in regulation of the im mune response. The functions of NK cells as well as their maturation a nd differentiation are regulated by various stimuli such as interleuki n-2 (IL-2) and interferon-alpha (IFN-alpha). The mechanisms by which t hese stimuli regulate distinct NK functions are not known. This study compared the patterns of gene expression for several NK-associated gen es namely perforin (PEF), granzymes A and B (GA or B), IL-1 beta, IFN- gamma, tumor necrosis factor-alpha (TNF-alpha), CD16 and NK-specific g enes, NKG2A, NKG5 and NKG7 in both unstimulated and in IL-2-, IFN-alph a- and PMA/Ionomycin (PMA/I)-stimulated NK cells purified from human p eripheral blood. IFN-alpha enhanced mRNA expression for PEF, IFN-gamma , TNF-alpha and NKG2A, but did not affect NKG7 mRNA expression. IL-2 a ugmented mRNA expression for PEF, IFN-gamma, TNF-alpha, NKG2A and NKG7 . PMA/I increased mRNA expression for IFN-gamma, TNF-alpha and NKG2A b ut did not affect mRNA expression for PEF and NKG7. Further, PMA/I inh ibited the expression of CD16 mRNA. These findings demonstrate that th e three NK-stimuli used share in common the regulation of several gene s but each regulates specifically other genes. These findings suggest that stimuli-specific expression of NK-associated genes may underlie t he molecular mechanisms responsible for distinct NK-mediated activitie s induced by different stimuli.