Oxygen radical-induced natural killer cell dysfunction: role of myeloperoxidase and regulation by serotonin

• Natural killer (NK) cells are functionally suppressed and induced to apoptosis by reactive oxygen species (ROS) produced by mononuclear phagocytes (MPs). These inhibitory events are reversed by the biogenic amine serotonin. MPs generate hydrogen peroxide (H(2)O(2)), which is processed further by myeloperoxidase (MPO) to even more toxic compounds. Earlier studies suggest that serotonin scavenges MP-derived oxygen radicals generated by the MPO-H(2)O(2) system. These findings led us to explore the capability of MPO-deficient MPs to induce NK cell dysfunction. We show that MPs recovered from subjects with MPO deficiency trigger inhibition of NK cells. In addition, MPs recovered from healthy subjects conveyed suppression of NK cells in the presence of the MPO inhibitor ceruloplasmin. We conclude that ROS-dependent inhibition of NK cell function is unrestricted by the availability of MPO-derived oxygen radicals and that the protecting properties of serotonin may operate in the absence of functional MPO. Our data suggest a complex mechanism of MP-induced NK cell inhibition, which comprises the generation of interchangeable oxygen radicals.

Nyckelord

Ceruloplasmin/pharmacology

Cytotoxicity

Immunologic

Free Radical Scavengers/*pharmacology

Humans

Hydrogen Peroxide/metabolism

K562 Cells

Killer Cells

Natural/*drug effects/enzymology

Lymphocytes/enzymology

Monocytes/cytology/immunology

NADPH Oxidase/metabolism

Peroxidase/antagonists & inhibitors/*physiology

Phagocytes

Reactive Oxygen Species/*metabolism

Research Support

Non-U.S. Gov't

Serotonin/*pharmacology

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