Cholesterol and its anionic derivatives inhibit 5-lipoxygenase activation in polymorphonuclear leukocytes and MonoMac6 cells.
5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes (LTs), biological mediators of host defense reactions and of inflammatory diseases. While the role of membrane binding in the regulation of 5-LO activity is well established, the effects of lipids on cellular activity when added to the medium has not been characterized. Here, we show such a novel function of the most abundant sulfated sterol in human blood, cholesterol sulfate (CS), to suppress LT production in human polymorphonuclear leukocytes (PMNL) and Mono Mac6 cells. We synthesized another anionic lipid, cholesterol phosphate, which demonstrated a similar capacity in suppression of LT synthesis in PMNL. Cholesteryl acetate was without effect. Cholesterol increased the effect of CS on 5-LO product synthesis. CS and cholesterol also inhibited arachidonic acid (AA) release from PMNL. Addition of exogenous AA increased the threshold concentration of CS required to inhibit LT synthesis. The effect of cholesterol and its anionic derivatives can arise from remodeling of the cell membrane, which interferes with 5-LO activation. The fact that cellular LT production is regulated by sulfated cholesterol highlights a possible regulatory role of sulfotransferases/sulfatases in 5-LO product synthesis.
Aleksandrov
Dmitry A
DA
A.N. Belozersky Institute of Physicochemical Biology, Moscow State University, Russia.
Zagryagskaya
Anna N
AN
Pushkareva
Marina A
MA
Bachschmid
Markus
M
Peters-Golden
Marc
M
Werz
Oliver
O
Steinhilber
Dieter
D
Sud'ina
Galina F
GF
D000838:Anions / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000302:isolation & purification / Q000378:metabolism*; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002746:Chlorpromazine / Q000494:pharmacology; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*
D000838:Anions; D002788:Cholesterol Esters; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D015638:Cytochalasin D; D016718:Arachidonic Acid; D000001:Calcimycin; C033095:cholesteryl phosphate; D002784:Cholesterol; D001094:Arachidonate 5-Lipoxygenase; C007045:cholesteryl sulfate; C060123:cholesterol acetate; D002746:Chlorpromazine