LYSIS-SENSITIVE TARGETS STIMULATE AN ELEVATION OF CAMP IN HUMAN NATURAL-KILLER-CELLS

Natural killer (NK) cells are lymphocytes that are capable of destroyi ng tumour cells and virally infected cells (cytolysis) without prior s ensitization. When cAMP is artificially elevated in NK cells, it is a potent inhibitor of their cytolytic Function. We investigated whether NK-cell cAMP levels are modulated in response to tumour target cells t o determine the potential of cAMP as a physiological regulator of NK c ytotoxic function. When NK cells are exposed to a range of lysis-sensi tive (LS) tumour-target cells there is an increase in intracellular cA MP levels in the NK cells over a 60-min period. The peak increase in c AMP (200-400% above control) occurs at 30 min for all LS targets teste d. There is no increase in NK-cell cAMP in response to lysis-resistant (LR) tumour-tar et cells. The cAMP elevation may be dependent on both LS-target-stimulated adenylyl cyclase (AC) activation and LS-target-s timulated phosphodiesterase (PDE) inhibition. When the NK cells are pr etreated with the protein tyrosine kinase (PTK) inhibitor, genistein ( 30 mu g/ml), the AC-activation component of the cAMP elevation is abol ished. Thus, the AC-activation component appears to require PTK activa tion. When NK cells are pretreated with the protein kinase C (PKC) inh ibitor, chelerythrine chloride (10 mu M) the cAMP elevation in respons e to LS targets was not diminished. This indicates that neither the AC -activation component nor any PDE-inhibition component require PDE-act ivation.