Leukotriene D-4 and prostaglandin E-2 signals synergize and potentiate vascular inflammation in a mast cell-dependent manner through cysteinyl leukotriene receptor 1 and E-prostanoid receptor 3

作者：Kondeti Vinay; Al Azzam Nosayba; Duah Ernest; Thodeti Charles K; Boyce Joshua A; Paruchuri Sailaja^*

来源：Journal of Allergy and Clinical Immunology, 2016, 137(1): 289-298.

DOI：10.1016/j.jaci.2015.06.030

• Mast cells
• prostaglandin E-2
• leukotriene D-4
• CysLT(1)R
• E-prostanoid receptor 3
• prostaglandin D-2
• c-fos
• protein kinase G
• extracellular signal-regulated kinase
• macrophage inflammatory protein 1 beta

Background: Although arachidonic acid metabolites, cysteinyl leukotrienes (cys-LTs; leukotriene [LT] C-4, LTD4, and LTE4), and prostaglandin (PG) E-2 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-PGE(2) crosstalk in inducing vascular inflammation in vivo, identify effector cells, and ascertain specific receptors and pathways involved in vitro.
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, PGD(2) and macrophage inflammatory protein 1 beta 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 PGE(2) potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in Kit(W-sh) mice. Furthermore, LTD4 plus PGE(2), through cysteinyl leukotriene receptor 1 (CysLT(1)R) and E-prostanoid receptor (EP) 3, enhanced extracellular signal-regulated kinase (Erk) and c-fos phosphorylation, inflammatory gene expression, macrophage inflammatory protein 1 beta secretion, COX-2 upregulation, and PGD(2) generation in mast cells. Additionally, we uncovered that this synergism is mediated through Gi, protein kinase G, and Erk signaling. LTD4 plus PGE(2)-potentiated effects are partially sensitive to CysLT(1)R or EP3 antagonists but completely abolished by simultaneous treatment both in vitro and in vivo.
Conclusions: Our results unravel a unique LTD4-PGE(2) interaction affecting mast cells through CysLT(1)R and EP3 involving Gi, protein kinase G, and Erk and contributing to vascular inflammation in vivo. Furthermore, current results also suggest an advantage of targeting both CysLT(1)R and EP3 in attenuating inflammation.

• 出版日期2016-1