Stimulus-dependent effects of CI-986 on arachidonic acid metabolism by human neutrophils

CI-986 (5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione, choline salt) was evaluated for its effect on arachidonic acid metabolism by human neutrophils in response to different stimuli. Leukotriene B₄ (LTB₄) release in response to calcium ionophore A23187 was 15 to 35 fold greater than the responses to N-formyl-methionyl-leucyl-phenylalanine (FMLP) or serum-opsonized zymosan (SOZ), respectively, while the thromboxane B₂ (TXB₂) release response was similar for the three stimuli tested. CI-986 inhibited the release of LTB₄ and TXB₂ in response to A23187 with IC₅₀s of 63.4 and 1.6 µM, respectively. In comparison, the compound inhibited SOZ-stimulated LTB₄ release with an IC₅₀ of 11.2µM, while having no effect on TXB₂ at concentrations up to 100 µM. Conversely, CI-986 inhibited FMLP-stimulated LTB₄ release by 42% at 100 µM, while inhibiting TXB₂ release with an IC₅₀ of 0.13 µM. These results demonstrate a stimulus-dependent inhibitory effect of CI-986 on human neutrophil eicosanoid metabolism.