Interferon Enhancement of Natural Killer Cell Cytotoxicity: Role of Cyclic Nucleotides

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Abstract
Treatment of either total mouse splenic lymphocytes, or populations of spleen cells which had been enriched for natural killer cell (NK) activity by passage through anti Ig or nylon wool columns, with electrophoretically pure mouse interferon caused a rapid (1–5 min) and transitory (duration 5–10 min) increase in the intracellular concentration of guanosine 3′5′-cyclic monophosphate (cyclic GMP). Electrophoretically pure human alpha interferon (HuIFN-α) was also found to increase the intracellular concentration of cyclic GMP in a morphologically homogenous population of large granular human lymphocytes which had been highly enriched for NK-cell activity by centrifugation on a discontinuous Percoll gradient. No consistent change in the intracellular concentration of adenosine 3′5′-cyclic monophosphate (cyclic AMP) was observed during the first 15–30 min following treatment of splenic lymphocytes with interferon. The IFN induced increase in cyclic GMP was calcium dependent and was inhibited by indomethacin and aspirin at concentrations of 10−7–10−5 M. Treatment of splenic lymphocytes with aspirin prior to the addition of interferon abrogated the interferon induced increase in cyclic GMP without preventing an increase in NK-cell activity. No significant increase in lymphocyte cytotoxicity was observed when mouse splenic lymphocytes were treated with compounds such as TPA, carbamylcholine, or sodium azide under the experimental conditions used in this study even though these compounds provoked an increase in the intracellular concentration of cyclic GMP comparable to that induced by interferon. An increase in cyclic GMP would therefore not appear to be necessary for the enhancement of NK cell activity by IFN although our results do not exclude the possibility that basal levels of cyclic GMP may be required for the establishment of NK cell cytotoxicity.