Zymosan suppresses leukotriene C4 synthase activity in differentiating monocytes: antagonism by aspirin and protein kinase inhibitors

J Esser, U Gehrmann, MD Salvado… - The FASEB …, 2011 - Wiley Online Library
J Esser, U Gehrmann, MD Salvado, A Wetterholm, JZ Haeggström, B Samuelsson…
The FASEB Journal, 2011Wiley Online Library
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) C4 synthase (LTC4S) in
differentiating monocytes, exposed for several days to fungal zymosan. Incubations with
LTA4 revealed 20‐fold increased LTC4S activity during differentiation of monocytic Mono …
Abstract
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) C4 synthase (LTC4S) in differentiating monocytes, exposed for several days to fungal zymosan. Incubations with LTA4 revealed 20‐fold increased LTC4S 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 LTC4S activity of primary human monocyte‐derived macrophages and dendritic cells. Several findings indicate phosphoregulation of LTC4S: increased activity during MM6 cell differentiation correlated with reduced phosphorylation of 70‐kDa ribosomal protein S6 kinase (p70S6K), which could phosphorylate purified LTC4S; the p70S6K inhibitor rapamycin (20 nM) doubled LTC4S activity of undifferentiated MM6 cells, and protein kinase A and C inhibitors (H‐89, CGP‐53353, and staurosporine) reversed the zymosan‐induced suppression of LTC4S activity. Finally, zymosan (48 h) up‐regulated PGE2 biosynthesis, and aspirin (10 µM) or prostaglandin E2 (PGE2) receptor antagonists counteracted the zymosan effect. Our results suggest a late PGE2‐mediated phosphoregulation of LTC4S during microbial exposure, which may contribute to resolution of inflammation, with implications for aspirin hypersensitivity.—Esser, J., Gehrmann, U., Salvado, M. D., Wetterholm, A., Haeggstrom,J. Z., Samuelsson, B., Gabrielsson, S., Scheynius, A., Rādmark, O. Zymosan suppresses leukotriene C4 synthase activity in differentiating monocytes: antagonism by aspirin and protein kinase inhibitors. FASEBJ. 25, 1417–1427 (2011). www.fasebj.org
Wiley Online Library