Leukotriene D₄ and prostaglandin E₂ signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3

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• 作者：Vinay Kondeti ; PhD^a ; Nosayba Al-Azzam ; MS^a ; Ernest Duah ; MS^a ; Charles K. Thodeti ; PhD^b ; Joshua A. Boyce ; MD^c ; ^d ; ^e ; Sailaja Paruchuri ; PhD^a ; ^{sp97@uakron.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Mast cells ; prostaglandin E2 ; leukotriene D4 ; CysLT1R ; E-prostanoid receptor 3 ; prostaglandin D2 ; c-fos ; protein kinase G ; extracellular signal-regulated kinase ; macrophage inflammatory protein 1β
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：137
• 期：1
• 页码：289-298
• 全文大小：2233 K

文摘

Although arachidonic acid metabolites, cysteinyl leukotrienes (cys-LTs; leukotriene [LT] C₄, LTD₄, and LTE₄), and prostaglandin (PG) E₂ are generated at the site of inflammation, it is not known whether crosstalk exists between these 2 classes of inflammatory mediators.

Objective

We sought to determine the role of LTD₄-PGE₂ crosstalk in inducing vascular inflammation m>in vivom>, identify effector cells, and ascertain specific receptors and pathways involved m>in vitrom>.

Methods

Vascular (ear) inflammation was assessed by injecting agonists into mouse ears, followed by measuring ear thickness and histology, calcium influx with Fura-2, phosphorylation and expression of signaling molecules by means of immunoblotting, PGD₂ and macrophage inflammatory protein 1β generation by using ELISA, and expression of transcripts by using RT-PCR. Candidate receptors and signaling molecules were identified by using antagonists and inhibitors and confirmed by using small interfering RNA.

Results

LTD₄ plus PGE₂ potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in m>Kitm>^m>W-shm> mice. Furthermore, LTD₄ plus PGE₂, through cysteinyl leukotriene receptor 1 (CysLT₁R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1β secretion, COX-2 upregulation, and PGD₂ generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD₄ plus PGE₂–potentiated effects are partially sensitive to CysLT₁R or EP₃ antagonists but completely abolished by simultaneous treatment both m>in vitrom> and m>in vivom>.

Conclusions

Our results unravel a unique LTD₄-PGE₂ interaction affecting mast cells through CysLT₁R and EP₃ involving Gi, protein kinase G, and Erk and contributing to vascular inflammation m>in vivom>. Furthermore, current results also suggest an advantage of targeting both CysLT₁R and EP₃ in attenuating inflammation.