Zymosan suppresses leukotriene C4synthase activity in differentiating monocytes: antagonism by aspirin and protein kinase inhibitors

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Cysteinyl leukotrienes (cysLTs) are potent proinflammatory mediators with particular relevance for asthma. However, control of cysLT biosynthesis in the time period after onset of acute inflammation has not been extensively studied. As a model for later phases of inflammation, we investigated regulation of leukotriene (LT) C(4) synthase (LTC(4)S) in differentiating monocytes, exposed for several days to fungal zymosan. Incubations with LTA(4) revealed 20-fold increased LTC(4)S activity during differentiation of monocytic Mono Mac 6 (MM6) cells, which was reduced by 80% in the presence of zymosan (25 μg/ml, 96 h). Zymosan (48 h) similarly attenuated LTC(4)S activity of primary human monocyte-derived macrophages and dendritic cells. Several findings indicate phosphoregulation of LTC(4)S: increased activity during MM6 cell differentiation correlated with reduced phosphorylation of 70-kDa ribosomal protein S6 kinase (p70S6K), which could phosphorylate purified LTC(4)S; the p70S6K inhibitor rapamycin (20 nM) doubled LTC(4)S activity of undifferentiated MM6 cells, and protein kinase A and C inhibitors (H-89, CGP-53353, and staurosporine) reversed the zymosan-induced suppression of LTC(4)S activity. Finally, zymosan (48 h) up-regulated PGE(2) biosynthesis, and aspirin (10 μM) or prostaglandin E(2) (PGE(2)) receptor antagonists counteracted the zymosan effect. Our results suggest a late PGE(2)-mediated phosphoregulation of LTC(4)S during microbial exposure, which may contribute to resolution of inflammation, with implications for aspirin hypersensitivity.