Absence of modulation of monokine production via endogenous cyclooxygenase or 5-lipoxygenase metabolites: MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid), indomethacin, or arachidonate fail to alter immunoreactive interleukin-1 beta, or TNF-alpha production by human monocytes in vitro.
Human peripheral blood monocytes exposed to MK-886 (3-[1-(4-chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2- dimethylpropanoic acid) at doses which abolish formation of 5-lipoxygenase metabolites showed unaltered interleukin-1 beta (IL-1 beta) or tumor necrosis factor-alpha (TNF-alpha) levels in response to phorbol ester, concanavalin A, serum-treated zymosan, or lipopolysaccharide. Indomethacin (10 microM), alone or in combination with MK-886, also failed to modulate monokine production in response to any stimulus. Exogenous arachidonate (3-30 microM) which augmented the formation of PGE2 and LTB4 in the absence of stimulation, also had no effect on monokine production. LPS-induced IL-1 and TNF production occurred despite stimulation of PGE2 synthesis. The results make a role for endogenous prostaglandins and leukotrienes in the regulation of monocyte IL-1 beta and TNF-alpha production unlikely. These data also indicate that MK-886, a novel inhibitor of 5-lipoxygenase product formation, is a potentially useful leukotriene inhibitor which does not affect monokine production.
Hoffman
T
T
Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Lee
Y L
YL
Lizzio
E F
EF
Tripathi
A K
AK
Jessop
J J
JJ
Taplits
M
M
Abrahamsen
T G
TG
Carter
C S
CS
Puri
J
J
D000704:Analysis of Variance; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism / Q000502:physiology*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology*; D003208:Concanavalin A / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D007375:Interleukin-1 / Q000096:biosynthesis*; D020024:Leukotriene Antagonists; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism / Q000502:physiology*; D011863:Radioimmunoassay; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015054:Zymosan / Q000494:pharmacology; D002722:Chlorobenzenes
D001094:Arachidonate 5-Lipoxygenase; D016718:Arachidonic Acid; D001095:Arachidonic Acids; D003208:Concanavalin A; D015232:Dinoprostone; D007211:Indoles; D007213:Indomethacin; D007375:Interleukin-1; D020024:Leukotriene Antagonists; D008070:Lipopolysaccharides; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate; D014409:Tumor Necrosis Factor-alpha; D015054:Zymosan; C060893:MK-886; D002722:Chlorobenzenes