Regulation of Prostaglandin E2 signaling by cysteinyl leukotrienes in human mast cells

Abstract

Cysteinyl leukotrienes (cys‐LTs), LTC4, LTD4 and LTE4, are critical mediators of airway hyper‐responsiveness and asthma. We have previously shown that LTD4 regulates mast cell (MCs) functions through the activation of G‐protein‐coupled receptors, CysLT1R and CysLT2R. The role of Prostaglandin E2 (PGE2), the other arachidonic acid metabolite in asthma is controversial as it act as both pro‐ and anti‐inflammatory, depending on the receptor through which it exerts its effect. Although cysLTs were shown to induce PGD2 generation in mast cells, it is not known whether there is cross‐talk between cysLTs and PGE2. Here, we found that PGE2 by itself does not activate calcium and MIP‐1β in mast cells, but cys‐LT priming induced robust PGE2‐dependent calcium flux and MIP‐1β generation. Further, using immunoprecipitation assays, we found that PGE2 receptor EP1R interacts with CysLT1R and this interaction was enhanced upon LTD4 stimulation. Importantly, we found that LTD4 and PGE2 synergistically increased the production of pro‐inflammatory cytokine, MIP1β in mast cells which was substantially inhibited by blocking protein kinase C (PKC)s. Taken together, our results suggest that cysLTs augment inflammation by activating PGE2 signaling through the priming of PGE2 receptors. This unravels a novel phenomenon by which inflammatory mediators generated from the same precursor can cooperate to enhance inflammation.