Inhibition of NK cell-mediated cytotoxicity by oxysterols.
Some of the oxidation products of cholesterol (oxysterols) have profound effects on plasma membrane structure and function. The present studies were undertaken to determine the effects of oxysterols on NK cell-mediated cytotoxicity. When mouse spleen cells were preincubated with certain oxysterols, NK cell cytotoxicity was inhibited without loss of effector cell viability. The strongest inhibition was observed with oxysterols that are oxidized at the C-5, C-6, or C-7 positions of the sterol nucleus. Among these, 7 beta-hydroxycholesterol caused more inhibition than 7 alpha-hydroxycholesterol suggesting that the spatial orientation of the hydroxyl group in the beta-position results in a greater perturbation in plasma membrane structure than that oriented in the alpha-position. In contrast, oxysterols that are oxidized at the C-20 and C-25 positions that are located on the C-17 acyl chain had little or no inhibitory effect, suggesting that oxidation in the cholesterol nucleus which is situated closer to the phospholipid headgroups at the lipid bilayer-aqueous interface results in a more profound effect on the plasma membrane physical structure. These results suggest that the lytic function of NK cell is sensitive to alterations in the physical state of its plasma membrane induced by oxysterols.
Kucuk
O
O
Section of Hematology/Oncology, Chicago Medical School, Illinois.
Stoner-Picking
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J
Yachnin
S
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Gordon
L I
LI
Williams
R M
RM
Lis
L J
LJ
Westerman
M P
MP
D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006888:Hydroxycholesterols / Q000494:pharmacology; D007653:Ketocholesterols / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008074:Lipoproteins / Q000494:pharmacology; D008214:Lymphocytes; D008297:Male; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D013154:Spleen / Q000166:cytology
D006888:Hydroxycholesterols; D007653:Ketocholesterols; D008074:Lipoproteins; C063833:6-ketocholestanol