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Activation of the human neutrophil 5‐lipoxygenase by leukotriene B 4
Author(s) -
McDonald Patrick P.,
McColl Shaun R.,
Naccache Paul H.,
Borgeat Pierre
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14491.x
Subject(s) - pertussis toxin , chemistry , leukotriene , receptor , arachidonic acid , leukotriene d4 , arachidonate 5 lipoxygenase , leukotriene b4 , stimulation , hydroxyeicosatetraenoic acid , endogeny , lipoxygenase , antagonist , microbiology and biotechnology , biochemistry , enzyme , g protein , biology , immunology , endocrinology , inflammation , asthma
1 In the present study, we demonstrate that leukotriene B 4 (LTB 4 ) has the ability to activate the human neutrophil 5‐lipoxygenase (5‐LO). 2 Stimulation of neutrophils with 30 n m 14,15‐dideuterio‐LTB 4 (D 2 ‐LTB 4 ) failed to induce the synthesis of LTB 4 from endogenous arachidonic acid (AA), but stimulated the formation of LTB 4 from 3.3 μ m exogenous AA, as determined by GC‐MS analysis. 3 The stimulatory effect of LTB 4 on 5‐LO activity was further examined with an alternative substrate; LTB 4 time‐ and dose‐dependently stimulated the 5‐LO‐mediated conversion of exogenous 15(S)‐hydroperoxy‐5,8,11,13‐(Z,Z,Z,E)‐eicosatetraenoate (15‐HpETE) into 5(S), 15(S)‐dihydroxy‐6,8,11,13,‐(E,Z,Z,E)‐eicosatetraenoate (5,15‐DiHETE), with a threshold effect at 300 p m . 4 The ability of LTB 4 to activate the 5‐LO showed structural specificity, since LTB 4 was found to be 100 times more potent than ω‐hydroxy‐LTB 4 , and 300 times more potent than its Δ 6 ‐ trans ‐12‐epi‐ isomer. 5 The LTB 4 ‐induced 5‐LO activation was effectively inhibited by MK‐886 (an inhibitor of 5‐LO translocation), by pertussis toxin, and by the LTB 4 receptor antagonist, LY‐223982. 6 These results demonstrate that the binding of LTB 4 to its cell‐surface receptor results in 5‐LO activation in a process mediated by pertussis toxin‐sensitive guanine nucleotide‐binding proteins. Our data also suggest that the underlying mechanism involves a translocation of the 5‐LO to the membrane. These findings raise the possibility that LTB 4 produced by phagocytes may positively feedback on its own synthesis.