Inhibition of human neutrophils by auranofin: chemotaxis and metabolism of arachidonate via the 5-lipoxygenase pathway.
The effect of auranofin on human neutrophil (PMN) 5-lipoxygenase activity and leucotriene B4 (LTB4) chemotaxis was investigated. [1-14C]Arachidonic acid was incorporated into the purified cells until steady state conditions were obtained. After preincubations with serial dilutions of auranofin arachidonic acid release and metabolism were stimulated with calcium ionophore A23187. The radioactive eicosanoids released were extracted and separated by thin layer chromatography, followed by autoradiography and quantitative laser densitometry. Chemotaxis of PMNs towards LTB4 was measured in a modified Boyden chamber. Auranofin showed dose dependent inhibition of both the 5-lipoxygenase pathway (IC50 17.4 X 10(-6) mol/l) and of chemotaxis (IC50 45 X 10(-6) mol/l). The release of arachidonic acid from phospholipids was unaffected in the concentration range tested (1-1000 mumol/l). Inhibition of both neutrophil motility and cellular synthesis of proinflammatory eicosanoids may thus contribute to the beneficial clinical effects of auranofin in rheumatoid arthritis.
Elmgreen
J
J
Department of Rheumatology TTA, Rigshospitalet, University of Copenhagen, Denmark.
Ahnfelt-Rønne
I
I
Nielsen
O H
OH
D001094:Arachidonate 5-Lipoxygenase / Q000097:blood; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000097:blood*; D001310:Auranofin / Q000494:pharmacology*; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D007975:Leukotriene B4 / Q000097:blood; D016859:Lipoxygenase Inhibitors; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism
D001095:Arachidonic Acids; D016859:Lipoxygenase Inhibitors; D007975:Leukotriene B4; D016718:Arachidonic Acid; D001310:Auranofin; D001094:Arachidonate 5-Lipoxygenase