Natural killer cell activity in the peripheral blood of patients with Cushing's syndrome

Abstract

Background: Natural killer (NK) cells are CD3-CD16+CD56+ bone- marrow-derived lymphocytes mediating first-line defence by direct cytotoxicity against various types of target cells without prior immunization. NK cell activity is positively regulated by immune interferon (IFN-γ); among hormones, glucocorticoids are potent in vitro and in vivo inhibitors, whereas ACTH and β-endorphin in many experimental circumstances enhance NK cytotoxicity. Design: We measured NK cytotoxicity of peripheral blood mononuclear cells (PBMC) obtained at 0800 h and 2000 h from 26 patients with Cushing's syndrome (12 pituitary-dependent, 12 adrenal-dependent and two dependent on ectopic ACTH secretion). In vitro responsiveness to IFN-γ or cortisol was also tested. Methods: NK activity was measured in a 4-h direct cytotoxicity assay using K562 cells as targets. Plasma ACTH, serum and urinary free cortisol were concomitantly measured with commercially available kits. Results: Spontaneous activity and responsiveness to IFN-γ, or cortisol were significantly greater in 15 age- and sex-matched controls than in Cushing's patients at 0800h. In pituitary-dependent Cushing's patients, plasma ACTH correlated positively with mean levels of spontaneous NK activity (r=0.64, P<0.05) and negatively with cortisol-dependent percentage inhibition (r=-0.69, P<0.02). In adrenal-dependent Cushing's patients, a negative correlation was observed between levels of spontaneous NK activity and urinary free cortisol (r=-0.67, P<0.02). Conclusions: Our data indicate that excess endogenous glucocorticoids affect spontaneous NK cell activity and responsiveness to exogenous IFN-γ or cortisol. The differential patterns observed between pituitary-dependent and adrenal-dependent groups are compatible with a positive immunomodulatory role of pituitary pro- opiomelanocortin-derived peptides that effectively counterbalance, at least partially, glucocorticoid immunosuppression.