Inhibition of human neutrophils by auranofin: chemotaxis and metabolism of arachidonate via the 5-lipoxygenase pathway

TY - JOUR

T1 - Inhibition of human neutrophils by auranofin

T2 - chemotaxis and metabolism of arachidonate via the 5-lipoxygenase pathway

AU - Elmgreen, J

AU - Ahnfelt-Rønne, I

AU - Nielsen, O H

PY - 1989/2

Y1 - 1989/2

N2 - 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.

AB - 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.

KW - Arachidonate 5-Lipoxygenase/blood

KW - Arachidonic Acid

KW - Arachidonic Acids/blood

KW - Auranofin/pharmacology

KW - Cells, Cultured

KW - Chemotaxis, Leukocyte/drug effects

KW - Humans

KW - Leukotriene B4/blood

KW - Lipoxygenase Inhibitors

KW - Neutrophils/drug effects

U2 - 10.1136/ard.48.2.134

DO - 10.1136/ard.48.2.134

M3 - Journal article

C2 - 2539060

SN - 0003-4967

VL - 48

SP - 134

EP - 138

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

IS - 2

ER -