Prostaglandin D(2) and leukotriene E(4) synergize to stimulate diverse T(H)2 functions and T(H)2 cell/neutrophil crosstalk

BACKGROUND: Prostaglandin D(2) (PGD(2)) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate T(H)2 cells. The combination of PGD(2) and cysLTs (notably cysteinyl leukotriene E(4) [LTE(4)]) enhances T(H)2 cytokine production. However, the synergistic interaction of cysLTs with PGD(2) in promoting T(H)2 cell activation is still poorly understood. The receptors for these mediators are drug targets in the treatment of allergic diseases, and hence understanding their interaction is likely to have clinical implications. OBJECTIVE: We aimed to comprehensively define the roles of PGD(2), LTE(4), and their combination in activating human T(H)2 cells and how such activation might allow the T(H)2 cells to engage downstream effectors, such as neutrophils, which contribute to the pathology of allergic responses. METHODS: The effects of PGD(2), LTE(4), and their combination on human T(H)2 cell gene expression were defined by using a microarray, and changes in specific inflammatory pathways were confirmed by means of PCR array, quantitative RT-PCR, ELISA, Luminex, flow cytometry, and functional assays, including analysis of downstream neutrophil activation. Blockade of PGD(2) and LTE(4) was tested by using TM30089, an antagonist of chemoattractant receptor-homologous molecule expressed on T(H)2 cells, and montelukast, an antagonist of cysteinyl leukotriene receptor 1. RESULTS: PGD(2) and LTE(4) altered the transcription of a wide range of genes and induced diverse functional responses in T(H)2 cells, including cell adhesion, migration, and survival and cytokine production. The combination of these lipids synergistically or additively enhanced T(H)2 responses and, strikingly, induced marked production of diverse nonclassical T(H)2 inflammatory mediators, including IL-22, IL-8, and GM-CSF, at concentrations sufficient to affect neutrophil activation. CONCLUSIONS: PGD(2) and LTE(4) activate T(H)2 cells through different pathways but act synergistically to promote multiple downstream effector functions, including neutrophil migration and survival. Combined inhibition of both PGD(2) and LTE(4) pathways might provide an effective therapeutic strategy for allergic responses, particularly those involving interaction between T(H)2 cells and neutrophils, such as in patients with severe asthma.