Chronic granulomatous disease (CGD) is characterized by severe, recurrent infections with bacteria and fungi, caused by a defect in the superoxide anion-producing NADPH-oxidase in polymorphonuclear (PMN) neutrophils. Treatment with interferon-gamma (IFN-γ) is associated with decreased frequency and severity of infections in CGD but the mechanism is unknown.

Objective of study: Since the inducible NO-synthase (iNOS) can be amplified by IFN-γ in e.g. murine macrophages, we hypothesized that IFN-γ might modulate nitric oxide (NO) release from CGD PMN.

Methods: Eight patients with CGD, 4 X-linked and 4 autosomal recessive, and eight matched healthy controls were studied. Each patient was given either 50 or 100 μg/m2 of IFN/γ on two consecutive days. Venous blood samples were obtained previous to IFN-γ and on day 1, 3 and 8 after the last dose. After activation with f-Met-Leu-Phe, the production of NO from PMN was assessed as the NG-monomethyl-L-arginine-inhibitable oxidation of oxyhemoglobin to methomoglobin in the presence of catalase and superoxide dismutase.

Results: Prior to IFN-γ treatment the CGD PMN produced 372±27 (mean±SEM) pmoles of NO/106 PMN at 45 minutes, compared with 343±44 pmoles (mean±SEM) of NO/106 PMN for control PMN. On day 1 after IFN-γ treatment, NO production increased to 132±25 percent of controls. On day 3 there was a maximal enhancement of NO production, 360%±37 (***) of controls. On day 8, the values remained higher, 280%±78, of controls. Although the formation of NO varied considerably between patients, the formation of NO was higher in all cases on day 3 than on days 0 and 1.

Conclusions: The present data strongly support the concept the IFN-γ treatment of CGD-patients is associated with an increased production of NO from PMN. Since these PMN lack the capacity to produce superoxide anions it is conceivable that this increase in NO release could be instrumental in augmenting host defense.