J W Darges, S P Robinson, L M Adams, Darges, J W, Robinson, S P, Adams, L M, Darges, James W., Robinson, Simon P., Adams, Laurel M.
Abstract
The sphingosine analog L-threo-dihydrosphingosine has been shown to inhibit protein kinase C (PKC) isoenzymes in mixed micelle and vesicle assays. This compound also inhibited the reactive oxygen intermediates (ROI) released from isolated neutrophils (IC50 approximately 2 microM) and phorbol ester-induced edema and neutrophil influx in the mouse ear model (ED50 approximately 11 mg/kg). Based on the anti-inflammatory activity of this compound, studies were done to determine its effect on arachidonate metabolism by the lipoxygenase pathway. Neutrophils were preincubated with test agents or vehicle for one minute and then incubated with 1 microM calcium ionophore A23187 for two minutes. Supernatants were assayed for LTB4 using a radioimmunoassay. The reference lipoxygenase inhibitor nordihydroguaiaretic acid exhibited 98.3% inhibition at 1 microM (n = 2) and prevented ROI production (IC50 approximately 6 microM). In contrast, the potent PKC inhibitor staurosporine was inactive against LTB4 in these studies (< 23% inhibition at 10 microM, n = 2), but inhibited ROI formation (IC50 approximately 3nM). L-threo-dihydrosphingosine inhibited LTB4 production 96.9 +/- 1.3%, at 10 microM (IC50 = 6 microM, n = 2). These data suggest that L-threo-dihydrosphingosine blocks the release of LTB4 from human neutrophils via a mechanism independent of PKC.
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