Decreased adenylyl cyclase and cAMP-dependent protein kinase activities inhibit the cytotoxic function of human natural killer cells

Abstract

Natural killer (NK) cells are lymphocytes that are capable of destroying tumor cells and virally infected cells without prior sensitization. Elevation of cyclic 3', 5' adenosine monophosphate (cAMP) levels in NK cells is known to cause dramatic inhibition of NK cytolytic function. However, the effect of lowering cellular levels of cAMP on the cytolytic function of natural killer (NK) cells has not been studied. The current study investigated the effects of inhibiting adenylyl cyclase (AC) or cAMP-dependent protein kinase (PKA) activities on the ability of NK cells to lyse K562 tumor cells, and on the activation of NK-cell phospholipase C (PLC) by tumor targets. Exposure of NK cells to the AC inhibitors MDL-12,330A (MDL) or 2',5',-Dideoxyadenosine (DDA) completely blocked their ability to destroy K562 tumor cells. Further, target-induced stimulation of NK-cell PLC was inhibited by as much as 90% when NK cells were treated with the AC inhibitors. Treatment of NK cells with the PKA inhibitor, H-89, caused essentially complete inhibition of cytotoxic function while decreasing target-induced stimulation of PLC by about 50%. Additionally, exposure to the organotin compound, tributyltin (TBT), which decreases cAMP levels in NK cells (as much as 80%) caused a decrease in cytotoxic function by as much as 90%. These data suggest that decreased levels of cAMP may cause very significant loss of NK cytotoxic function and that this may be mediated by decreased PKA activity. These data coupled with previous work revealing that increased cAMP levels inhibit NK cytotoxic function, suggest that tight regulation of cAMP levels is critical to NK cell function.