Mechanisms of human cell-mediated cytotoxicity. II. Correction of the selective defect in natural killing in the Chediak-Higashi syndrome with inducers of intracellular cyclic cGMP

P. Katz, J. C. Roder, A. M. Zaytoun, R. B. Herberman, A. S. Fauci

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

In this study we investigated the modulation by cyclic nucleotides of depressed natural killer (NK) cell activity in 2 patients with the Chediak-Higashi syndrome (CHS). Patients with CHS have defective NK function that is not attributable to a lack of effector cells or a defect in target cell binding. Because of the previously reported abnormalities of the levels of intracellular cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in these patients, we investigated the effects of exogenous cGMP or its intracellular inducers on CHS NK activity. The direct addition to peripheral blood mononuclear effector cell-K562 target cell mixtures of the cGMP inducers dibutyryl cGMP (DB-cGMP), 8-bromo-cGMP (8Br-cGMP), carbachol, acetylcholine, or ascorbic acid at the initiation of standard 4-hr 51chromium- (51Cr) release microcytotoxicity assay corrected the depression of CHS cytolytic function in a dose-dependent fashion. Phenylephrine, an α-adrenergic agent that lowers intracellular cAMP content, produced similar results. The relative increase in CHS NK activity was significantly greater than that observed with normal effector cells. The continuous presence of these cGMP inducers during the assay was not necessary for the abrogation of the killing defect to occur; preincubation of CHS mononuclear cells with cGMP inducers transiently increased cytotoxicity for up to 2 hr before returning to pretreatment levels. The cGMP-related increase in CHS natural killing occurred early in the 4-hr assay and the enhancement was demonstrable throughout this period. The cGMP-induced increase in CHS NK capacity could be reversed by specific cAMP antagonists in a concentration-dependent manner. Blockage of surface receptors for carbachol by atropine prevented the augmentation of CHS cytotoxicity by this cGMP inducer. The observed cytotoxic changes were not secondary to alterations in CHS effector cell viability or target cell binding. This study further underscores the importance of cyclic nucleotides as regulators of normal and abnormal NK activity and may be useful in developing means of increasing defective lytic activity in CHS patients and those individuals with demonstrable abnormalities of natural killing.

Original languageEnglish (US)
Pages (from-to)297-302
Number of pages6
JournalJournal of Immunology
Volume129
Issue number1
StatePublished - Sep 10 1982

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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