TARGET-EFFECTOR INTERACTION IN THE NATURAL KILLER CELL SYSTEM .4. MODULATION BY CYCLIC-NUCLEOTIDES

Abstract

Dibutyryl c[cyclic]AMP (dB-cAMP) and the cAMP elevating agents, prostaglandin (PG) E1, theophylline and histamine markedly suppressed [mouse] NK [natural killer] cell cytolytic function in a dose- and rate-dependent manner. Inhibition was rapidly induced and persisted in the presence of the drugs. Separate pre-treatment of targets and highly purified NK cells, isolated by a target binding and velocity sedimentation technique, revealed that PGE1 and dB-cAMP acted at the level of the effector cell in a short-term cytolytic assay. In contrast to the inhibitory effects of cAMP elevating agents, dB-cGMP and carbamylcholine caused a small but significant acceleration in rate of lysis and could compete with inhibitory doses of dB-cAMP to reduce the level of suppression, suggesting that the cAMP-cGMP ratio might be important in NK cell-mediated lysis. Insulin had no effect on NK cell activity whereas T [thymus-derived] cell-mediated cytolysis was augmented by insulin and cGMP if the effector cells were taken early after alloimmunization. Neither cAMP-nor cGMP-elevating agents affected the frequency of NK-target cell conjugates. Cyclic nucleotides may be involved in triggering the lytic event within NK cells.