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 against infection and cancer and also participate in regulation of the immune response. The functions of NK cells as well as their maturation and differentiation are regulated by various stimuli such as interleukin-2 (IL-2) and interferon-alpha (IFN-alpha). The mechanisms by which these stimuli regulate distinct NK functions are not known. This study compared the patterns of gene expression for several NK-associated genes namely perforin (PEF), granzymes A and B (GA or B), IL-1beta, IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), CD16 and NK-specific genes, NKG2A, NKG5 and NKG7 in both unstimulated and in IL-2-, IFN-alpha and PMA/Ionomycin (PMA/I)-stimulated NK cells purified from human peripheral blood. IFN-alpha enhanced mRNA expression for PEF, IFN-gamma, TNF-alpha and NKG2A, but did not affect NKG7 mRNA expression. IL-2 augmented mRNA expression for PEF, IFN-gamma, TNF-alpha, NKG2A and NKG7. PMA/I increased mRNA expression for IFN-gamma, TNF-alpha and NKG2A but did not affect mRNA expression for PEF and NKG7. Further, PMA/I inhibited the expression of CD16 mRNA. These findings demonstrate that the three NK-stimuli used share in common the regulation of several genes but each regulates specifically other genes. These findings suggest that stimuli-specific expression of NK-associated genes may underlie the molecular mechanisms responsible for distinct NK-mediated activities induced by different stimuli.