Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk

Abstract

BackgroundProstaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 and cysLTs (notably cysteinyl leukotriene E4 [LTE4]) enhances TH2 cytokine production. However, the synergistic interaction of cysLTs with PGD2 in promoting TH2 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.ObjectiveWe aimed to comprehensively define the roles of PGD2, LTE4, and their combination in activating human TH2 cells and how such activation might allow the TH2 cells to engage downstream effectors, such as neutrophils, which contribute to the pathology of allergic responses.MethodsThe effects of PGD2, LTE4, and their combination on human TH2 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 PGD2 and LTE4 was tested by using TM30089, an antagonist of chemoattractant receptor-homologous molecule expressed on TH2 cells, and montelukast, an antagonist of cysteinyl leukotriene receptor 1.ResultsPGD2 and LTE4 altered the transcription of a wide range of genes and induced diverse functional responses in TH2 cells, including cell adhesion, migration, and survival and cytokine production. The combination of these lipids synergistically or additively enhanced TH2 responses and, strikingly, induced marked production of diverse nonclassical TH2 inflammatory mediators, including IL-22, IL-8, and GM-CSF, at concentrations sufficient to affect neutrophil activation.ConclusionsPGD2 and LTE4 activate TH2 cells through different pathways but act synergistically to promote multiple downstream effector functions, including neutrophil migration and survival. Combined inhibition of both PGD2 and LTE4 pathways might provide an effective therapeutic strategy for allergic responses, particularly those involving interaction between TH2 cells and neutrophils, such as in patients with severe asthma.

Enhancing capillary blood collection: The influence of nicotinic acid and nonivamide

“…It has previously been suggested that nicotinic acid and nonivamide topical cream may modulate the activity of local immune cells, including granulocytes and TH 2 cells . However, our study identified no influence of this mechanism of enhancing capillary flow on either the local leucocyte subpopulations or granulocytic functional‐related surface antigen markers.…”

“…During allergy states, this prostanoid induces a vasodilatory response, increases vessel permeability, and mediates the activity of effector cells such as helper T cells, eosinophils, basophils, mast cells, and dendritic cells . Furthermore, in combination with cysteinyl leukotriene E 4 (LTE 4 ), PGD 2 is capable of altering adhesion, migration, and cytokine production by helper T cells …”

DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator

“…PGD 2 has been shown to regulate apoptosis in a cell type specific manner. It protects Th2 cells from cytokine deprivation‐induced apoptosis via DP2 signaling, and antagonizes PGE 2 ‐mediated Bax activation and hence inhibits the induction of apoptosis in glioma cells . In contrast, PGD 2 induces apoptosis in human osteoclasts, leukemia cells and non‐small cell lung carcinoma cell lines .…”

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

“…Interestingly, PGD 2 has been recently shown to synergize with LTE 4 to stimulate diverse T H 2 functions and T H 2 cell and neutrophil crosstalk. 35,36 It is possible that during inflammation, LTD 4 plus PGE 2 treatment not only activates MCs and initiates inflammation, but also the product of this signaling, PGD 2 , can potentially perpetuate inflammation through combined action with LTE 4 . Both LTD 4 and PGE 2 have been demonstrated to phosphorylate Erk in MCs.…”