PARADOXICAL EFFECTS OF COLCHICINE ON THE ACTIVATION OF HUMAN NEUTROPHILS BY CHEMOTACTIC FACTORS AND INFLAMMATORY MICROCRYSTALS

Neutrophil activation by chemotactic factors and by inflammatory micro crystals is accompanied by increases in protein tyrosine phosphorylati on and by the activation of the NADPH oxidase. The addition of colchic ine inhibited both responses induced by triclinic monosodium mate or c alcium pyrophosphate crystals. On the other hand, colchicine enhanced the tyrosine phosphorylation of specific protein in neutrophils stimul ated by chemotactic factor and augmented the production of superoxide anions induced by these same agonists, The effects of colchicine were shared by other anti-microtubule agents (nocodazole and vinblastine) b ut not by its inactive analogue beta-lumicolchicine, trimethylcolchici nic acid, indomethacin, or phenylbutazone. Furthermore, the (enhancing as well as inhibitory) effects of colchicine on tyrosine phosphorylat ion and superoxide anion production were reversed by taxol, Finally, i n human cytoplasts colchicine again inhibited microcrystal-stimulated tyrosine phosphorylation but did not change chemotactic factor-stimula ted phosphorylation. These data strongly support the hypothesis that m icrotubule-related mechanisms are involved in the modulation of the ty rosine phosphorylation response in human neutrophils, and suggest that a relationship, may exist between the augmentation of tyrosine phosph orylation and of the stimulation of the NADPH oxidase induced by chemo tactic factors.