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.
Betten
Asa
A
Göteborg University, Guldhedsgatan 10 B, S-413 46 Göteborg, Sweden. Aasa.Betten@microbio.gu.se
Dahlgren
Claes
C
Mellqvist
Ulf-Henrik
UH
Hermodsson
Svante
S
Hellstrand
Kristoffer
K
D002570:Ceruloplasmin / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D016166:Free Radical Scavengers / Q000494:pharmacology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000201:enzymology; D008214:Lymphocytes / Q000201:enzymology; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D019255:NADPH Oxidases / Q000378:metabolism; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000502:physiology*; D010586:Phagocytes; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology*
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D012701:Serotonin; D006861:Hydrogen Peroxide; D009195:Peroxidase; D002570:Ceruloplasmin; D019255:NADPH Oxidases