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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:135

Article

Xue, Luzheng^1,2  Fergusson, Joannah³  Salimi, Maryam^1,4  Panse, Isabel¹  Ussher, James E.³  Hegazy, Ahmed N.⁵  Vinall, Shan L.⁶  Jackson, David G.⁴  Hunter, Michael G.⁶  Pettipher, Roy⁶  Ogg, Graham^1,4  Klenerman, Paul^1,3 

[1] Univ Oxford, John Radcliffe Hosp, Oxford NIHR Biomed Res Ctr, Nuffield Dept Med,Translat Immunol Lab, Oxford OX3 9DU, England

[2] Univ Oxford, Nuffield Dept Med, Resp Med Unit, Oxford OX3 9DU, England

[3] Univ Oxford, Nuffield Dept Med, Peter Medawar Bldg Pathogen Res, Oxford OX3 9DU, England

[4] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford OX3 9DU, England

[5] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Med, Translat Gastroenterol Unit, Oxford OX3 9DU, England

[6] Atopix Therapeut Ltd, Abingdon, Oxon, England

关键词: Prostaglandin D-2;    leukotriene E-4;    chemoattractant receptor-homologous molecule expressed on T(H)2 cells;    T(H)2 cells;    neutrophils;   

DOI  :  10.1016/j.jaci.2014.09.006

来源: Elsevier

【 摘 要 】

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 [LTE4]) 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), LTE4, 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), LTE4, 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 LTE4 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 LTE4 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 GMCSF, at concentrations sufficient to affect neutrophil activation. Conclusions: PGD(2) and LTE4 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 LTE4 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.

【 授权许可】

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