Cytokine-induced endogenous production of prostaglandin D2 is essential for human group 2 innate lymphoid cell activation

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:143

Article

Maric, Jovana^1,2,3  Ravindran, Avinash^7,8  Mazzurana, Luca³  Van Acker, Aline³  Rao, Anna³  Kokkinou, Efthymia³  Ekoff, Maria^7,8  Thomas, Dominique⁹  Fauland, Alexander⁴  Nilsson, Gunnar^7,8,10  Wheelock, Craig E.⁴  Dahlen, Sven-Erik⁵  Ferreiros, Nerea⁹  Geisslinger, Gerd^9,11  Friberg, Danielle^6,12  Heinemann, Akos^1,2  Konya, Viktoria^1,2,3  Mjosberg, Jenny^3,13 

[1] Med Univ Graz, Otto Loewi Res Ctr, Pharmacol Sect, Graz, Austria

[2] BioTechMed, Graz, Austria

[3] Karolinska Inst, Dept Med Huddinge, Ctr Infect Med, Stockholm, Sweden

[4] Karolinska Inst, Dept Med Biochem & Biophys, Div Physiol Chem 2, Stockholm, Sweden

[5] Karolinska Inst, Inst Environm Med, Expt Asthma & Allergy Res, Stockholm, Sweden

[6] Karolinska Inst, Dept Clin Sci Intervent & Technol, CLINTEC, Stockholm, Sweden

[7] Karolinska Inst, Dept Med, Immunol & Allergy Unit, Solna, Sweden

[8] Karolinska Univ Hosp, Clin Immunol & Transfus Med, Stockholm, Sweden

[9] Goethe Univ Frankfurt, Inst Clin Pharmacol, Pharmazentrum Frankfurt ZAFES, Frankfurt, Germany

[10] Uppsala Univ, Dept Med Sci, Uppsala, Sweden

[11] Fraunhofer Inst Mol Biol & Appl Ecol IME, Project Grp Translat Med & Pharmacol TMP, Frankfurt, Germany

[12] Uppsala Univ, Dept Surg Sci, Uppsala, Sweden

[13] Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden

关键词: Group 2 innate lymphoid cells;    prostaglandin D-2;    chemoattractant receptor-homologous molecule expressed on T(H)2 cells;    allergy;   

DOI  :  10.1016/j.jaci.2018.10.069

来源: Elsevier

【 摘 要 】

Objective: We set out to examine PG production in human ILC2s and the implications of such endogenous production on ILC2 function. Methods: The effects of the COX-1/2 inhibitor flurbiprofen, the hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor KMN698, and the CRTH2 antagonist CAY10471 on human ILC2s were determined by assessing receptor and transcription factor expression, cytokine production, and gene expression with flow cytometry, ELISA, and quantitative RT-PCR, respectively. Concentrations of lipid mediators were measured by using liquid chromatography-tandem mass spectrometry and ELISA. Results: We show that ILC2s constitutively express HPGDS and upregulate COX-2 upon IL-2, IL-25, and IL-33 plus thymic stromal lymphopoietin stimulation. Consequently, PGD2 and its metabolites can be detected in ILC2 supernatants. We reveal that endogenously produced PGD2 is essential in cytokine-induced ILC2 activation because blocking of the COX-1/2 or HPGDS enzymes or the CRTH2 receptor abolishes ILC2 responses. Conclusion: PGD2 produced by ILC2s is, in a paracrine/autocrine manner, essential in cytokine-induced ILC2 activation. Hence we provide the detailed mechanism behind how CRTH2 antagonists represent promising therapeutic tools for allergic diseases by controlling ILC2 function.

【 授权许可】

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