Various authentic chemoattractants mediating leukocyte adherence inhibition

This study resulted from the finding that cancer extract-induced leukocyte adherence inhibition (LAI) depends on release of arachidonic acid metabolites of which leukotriene B4 (LTB4) is a chemoattractant. Leukotrienes, the chemotactic fragment of the fifth component of complement (C5a des arg), N-formyl-L-methionylyl-L-leucyl-L-phenylalanine (FMLP), platelet-activating factor (PAF), and phorbol myristate acetate (PMA) increased the nonadherence of human leukocytes to glass with bell-shaped dose-response curves. For maximum nonadherence, the optimum concentration was about 2 X 10(-11) M LTB4, 10(-9) M C5a des arg, 2 X 10(-8) M FMLP, 2 X 10(-9) M PAF, and 2 X 10(-8) M PMA. Of the adherent leukocytes, 29% became nonadherent. Higher concentrations of leukotriene E4, FMLP, PAF, and PMA induced leukocyte hyperadhesiveness. Chemoattractant-induced LAI was antagonized by inhibitors of glycolysis, oxidative metabolism, electron transport, microfilaments, and microtubules, whereas the same concentration of inhibitors did not alter the adherence of leukocytes to glass in control tubes. T-cells, neutrophils, and mononuclear cells showed LAI to LTB4, C5a des arg, and FMLP. Moreover, no additive effect was observed when leukocytes exposed to a first chemoattractant at its optimum concentration were exposed to a second. A competitive inhibitor of leukotriene slow-reacting substance of anaphylaxis, FPL 55712, blocked in a dose-response fashion LTB4-, C5a des arg-, and FMLP-triggered LAI. Eicosatetraenoic acid and nordihydroguaiaretic acid, cyclo-oxygenase-lipoxygenase pathway inhibitors, also markedly antagonized LTB4-, C5a des arg-, and FMLP-triggered LAI. Indomethacin (10(-5) M), piroxicam (10(-6) M), and aspirin, cyclooxygenase antagonists, negated LTB4-, C5a des arg-, and FMLP-induced LAI. Prostaglandins E2, E1, and F2 and prostacyclin did not trigger LAI. However, selective thromboxane synthetase antagonists completely negated chemoattractant-triggered LAI. Our studies indicated that chemoattractants stimulated leukocytes to produce thromboxanes, which increased leukocyte nonadherence.