Mechanisms of human cell-mediated cytotoxicity. I. Modulation of natural killer cell activity by cyclic nucleotides

P. Katz, A. M. Zaytoun, A. S. Fauci

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

In the present study we demonstrate the regulation and modulation of human natural killer (NK) cell activity by cyclic nucleotides and their intracellular inducers. The direct addition of the cyclic adenosine monophosphate- (cAMP) inducers dibutyryl cAMP (DB-cAMP), isoproterenol, aminophylline, or histamine to peripheral blood mononuclear cell-K562 cell mixtures at the initiation of a 4-hr 51chromium-release microcytotoxicity assay significantly suppressed NK function in a dose-dependent manner. Cyclic guanosine monophosphate (cGMP) analogs or compounds known to increase the cGMP content of lymphocytes produced a small but significant enhancement of cytotoxic activity. The continuous presence of these agents during the assay was not required for the observed effect. The cAMP and cGMP-induced alteration of killing occurred relatively early in the lytic process and the effects were apparent throughout the assay. Preincubation of effector cells with cAMP or cGMP inducers before the NK assay produced transient, reversible modulation of lysis; the cyclic nucleotide-induced alteration in cytotoxicity lasted only 2 hr before returning to base-line pretreatment values. cAMP and cGMP-induced changes in NK activity were reversible by specific antagonists. Blockade of the surface neurohumoral receptors for isoproterenol and carbachol by propranolol and atropine, respectively, abrogated the attenuation of NK function induced by these autonomic agonists. Experiments employing highly purified fractions of NK-enriched large granular lymphocytes indicated that cAMP- and cGMP-inducing agents affected activity of cytotoxic lymphocytes directly rather than through effects on accessory non-lytic cells. The cyclic nucleotide-induced alterations in NK activity were not due to changes in effector cell viability, target cell binding, or the susceptibility of target cells to lysis. These studies demonstrate the important roles of cyclic nucleotides in modulating NK function and may provide the basis for the eventual elucidation and manipulation of cytotoxic activity in normal and disease states.

Original languageEnglish (US)
Pages (from-to)287-296
Number of pages10
JournalJournal of Immunology
Volume129
Issue number1
StatePublished - 1982

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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