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.

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

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.

LTD₄ plus PGE₂ potentiated vascular permeability and edema, gearing the system toward proinflammation in wild-type mice but not in Kit^W-sh 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 in vitro and in vivo.

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 in vivo. Furthermore, current results also suggest an advantage of targeting both CysLT₁R and EP₃ in attenuating inflammation.