Pharmacological inhibition of eicosanoids and platelet-activating factor signaling impairs zymosan-induced release of IL-23 by dendritic cells

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• 作者：Mario Rodrí ; guez^a ; Saioa Má ; rquez^a ; Olimpio Montero^b ; Sara Alonso^c ; Javier Garcí ; a Frade^d ; Mariano Sá ; nchez Crespo^c ; ^{mscres@ibgm.uva.es" class="auth_mail" title="E-mail the corresponding author} ; Nieves Ferná ; ndez^a
• 关键词：Acetyl-CoA (PubChem CID ; 444493) ; Arachidonoyl-CoA (PubChem CID ; 52922027) ; Darapladib (PubChem CID ; 9939609) ; EDC (2-TEDC ; PubChem CID ; 6069552) ; 12-HETE (PubChem CID ; 5353272) ; 12-HETE-d8 (PubChem CID ; 1436) ; Leukotriene B4 (PubChem CID ; 5280492) ; Leukotriene B4-d4 (PubChem CID ; 53394387) ; Leukotriene C4 (PubChem CID ; 5280493) ; Leukotriene E4 (PubChem CID ; 5280879) ; Lyso-PAF C16 ; 0 (PubChem CID ; 3983) ; Montelukast (PubChem CID ; 5281040) ; PGE2 (PubChem CID ; 5280360) ; Platelet-activating factor (
• 刊名：Biochemical Pharmacology
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：102
• 期：Complete
• 页码：78-96
• 全文大小：4703 K

文摘

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.