Effects of vitamin K on human neutrophil function.

Abstract

The effects of Vitamin (Vit) K on human neutrophils (PMN) were studied. Vit K3 and Vit K5 inhibited neutrophil spreading, locomotion, phagocytosis, degranulation of lysosomal constitutents, bactericidal activity, superoxide generation, and hydrogen peroxide production. The concentration of Vit K3 producing 50% inhibition of these functions was = 10−5 M. Vit K3 also inhibited microtubule assembly. Vit K3 did not affect the expression of Fc or C3b receptors in an erythrocyte rosetting assay. However, accumulation of the chemoattractant f-met-leu-(3H)phe was inhibited by Vit K3 and was secondary to inhibition of ligand internalization without a significant effect on the availability of surface receptors assessed by specific displaceable and nondisplaceable f-met-leu-(3H)phe binding. These Vit K3 effects were associated with stimulation of the hexose monophosphate shunt in PMN obtained from both normal subjects and from patients with chronic granulomatous disease. Vit K3 also caused a small stimulation of basal oxygen uptake but inhibited large stimulated oxygen uptake in response to secretagogues or f-met-leu-phe. Vit K3 did not inhibit glycolysis as monitored by lactic acid production. In addition to these effects Vit K3 inhibited PMN activation, detected with the membrane potential sensitive fluorescent probe, di-O-C5(3). Vit K3 did not affect 45Ca++ uptake, but amplified chemoattractant-stimulated calcium (45Ca++) release. The inhibition of PMN functions by Vit K3 was prevented by reduced glutathione (1 mM) but not dithiothreitol, tetrachloropyridine, ascorbic acid, or dicoumarol. Vit K1 and other related naphthoquinones, as well as quinones such as coenzyme Q, had no effect on PMN. The inhibitory effects of the active forms of Vit K may result from several mechanisms. These include oxidation or conjugation of vital sulfhydryl groups by Vit K epoxide, and reduction of the quinone portion of Vit K providing a potent electron acceptor that interferes with a normal electron cascade. Vit K and its derivatives appear to be valuable agents for probing the interrelated mechanisms involved in PMN activation.