2024-03-29T13:52:28Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/1580882022-05-03T11:56:43Zcom_10261_39com_10261_1col_10261_292
Rodríguez, Mario
Márquez, Saioa
Montero, Olimpio
Alonso, Sara
García Frade, Javier
Sánchez Crespo, Mariano
Fernández, Nieves
2017-12-12T08:08:08Z
2017-12-12T08:08:08Z
2016
Biochemical Pharmacology 102: 78-96 (2016)
http://hdl.handle.net/10261/158088
10.1016/j.bcp.2015.12.001
http://dx.doi.org/10.13039/100008054
http://dx.doi.org/10.13039/501100003329
http://dx.doi.org/10.13039/501100014180
The engagement of the receptors for fungal patterns induces the expression of cytokines, the release of arachidonic acid, and the production of PGE2 in human dendritic cells (DC), but few data are available about other lipid mediators that may modulate DC function. The combined antagonism of leukotriene (LT) B4, cysteinyl-LT, and platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) inhibited IL23A mRNA expression in response to the fungal surrogate zymosan and to a lower extent TNFA (tumor necrosis factor-α) and CSF2 (granulocyte macrophage colony-stimulating factor) mRNA. The combination of lipid mediators and the lipid extract of zymosan-conditioned medium increased the induction of IL23A by LPS (bacterial lipopolysaccharide), thus suggesting that unlike LPS, zymosan elicits the production of mediators at a concentration enough for optimal response. Zymosan induced the release of LTB4, LTE4, 12-hydroxyeicosatetraenoic acid (12-HETE), and PAF C16:0. DC showed a high expression and detectable Ser663 phosphorylation of 5-lipoxygenase in response to zymosan, and a high expression and activity of LPCAT1/2 (lysophosphatidylcholine acyltransferase 1 and 2), the enzymes that incorporate acetate from acetyl-CoA into choline-containing lysophospholipids to produce PAF. Pharmacological modulation of the arachidonic acid cascade and the PAF receptor inhibited the binding of P-71Thr-ATF2 (activating transcription factor 2) to the IL23A promoter, thus mirroring their effects on the expression of IL23A mRNA and IL-23 protein. These results indicate that LTB4, cysteinyl-LT, and PAF, acting through their cognate G protein-coupled receptors, contribute to the phosphorylation of ATF2 and play a central role in IL23A promoter trans-activation and the cytokine signature induced by fungal patterns.
eng
closedAccess
Dendritic cells
Signal transduction
Lipid mediators
Fungus
Cytokines
Pharmacological inhibition of eicosanoids and platelet-activating factor signaling impairs zymosan-induced release of IL-23 by dendritic cells
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