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Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk  Luzheng Xue, PhD, Joannah Fergusson,

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Presentation on theme: "Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk  Luzheng Xue, PhD, Joannah Fergusson,"— Presentation transcript:

1 Prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk  Luzheng Xue, PhD, Joannah Fergusson, BSc, Maryam Salimi, MD, Isabel Panse, BTA, James E. Ussher, PhD, FRCPA, Ahmed N. Hegazy, MD, PhD, Shân L. Vinall, PhD, David G. Jackson, PhD, Michael G. Hunter, PhD, Roy Pettipher, PhD, Graham Ogg, DPhil, FRCP, Paul Klenerman, FMedSci  Journal of Allergy and Clinical Immunology  Volume 135, Issue 5, Pages e11 (May 2015) DOI: /j.jaci Copyright © 2014 The Authors Terms and Conditions

2 Fig 1 Gene regulation in TH2 cells by PGD2 and LTE4 detected by using a microarray. A, Venn diagram representing total numbers of genes regulated significantly. B, Venn diagrams and heat map showing numbers of genes downregulated or upregulated significantly. P < .05. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

3 Fig 2 Effects of PGD2 and LTE4 on the apoptosis and migration of TH2 cells. A, Detection of Annexin V in TH2 cells treated with IL-2 deprivation in the presence of compounds, as indicated. B, Cell migration in response to PGD2, LTE4, or LTD4 (left panel) or the combination of indicated compounds (right panel). *P < .05 between indicated treatments (Fig 2, A) or between PGD2 plus LTE4 and other treatments (Fig 2, B). n = 3. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

4 Fig 3 Involvement of integrins in CAIA of TH2 cells induced by PGD2 and LTE4. Cell aggregation after incubation with indicated treatments for 2 hours (A), for 2 or 9 hours in the presence of EDTA or MnCl2 (B), or for 1 hour in the presence of the indicated antibodies (C). Scale bar = 0.5 mm. *P < .05 between PGD2 plus LTE4 and other treatments or between indicated conditions (n = 2-5). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

5 Fig 4 PGD2 and LTE4 modulate gene transcription of cytokines, chemokines, and surface receptors in TH2 cells determined by means of microarray (A and B) or PCR array (C). Fig 4, A, Venn diagram and heat map showing the number and distribution of genes significantly regulated. Fig 4, B and C, Strongly upregulated genes. P < .05 (n = 3). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

6 Fig 5 Effects of PGD2 and LTE4 on production of selected cytokines in TH2 cells. A, Levels of mRNA measured by using qPCR. The mRNA levels in control samples were treated as 1-fold. B, Protein levels were detected with the Luminex assay. *P < .05 between PGD2 plus LTE4 and other conditions or the indicated condition (n = 3). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

7 Fig 6 TH2-derived cytokines activate neutrophils. A, IL-8 and GM-CSF levels in stimulated TH2 cell supernatants assigned as supernatants 1 (white bars), 2 (gray bars), and 3 (black bars, n = 4). B, Effect of supernatants (left panel), IL-8, PGD2, LTE4 (right panel), and anti–IL-8 antibody on neutrophil migration. C, Effect of supernatants and anti–GM-CSF antibody on expression of CD16 (left panel) and Annexin V (right panel) in neutrophils determined by using fluorescence-activated cell sorting. *P < .05 between the indicated treatment and other conditions (n = 2-7). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

8 Fig E1 Analysis of cell phenotype. A and B, Expanded TH2 cells were CD3+CD4+CRTH2+CD45RO+GATA3+CCR6−CCR7−CD45RA−RORγt− effector memory cells (Fig E1, A), which produce the type II cytokines IL-8 and IL-22 after stimulation with PMA (5 ng/mL) and ionomycin (500 ng/mL; Fig E1, B), as detected by means of flow cytometry. Blue lines represent staining of indicated cell markers, and red lines represent unstained controls. C, The same cytokine profile was observed in freshly isolated ex vivo TH2 cells by using qPCR (mRNA) and Luminex (protein) assays (high background IL-8 levels in the unstimulated sample precluded accurate analysis of this cytokine in the Luminex assay; n = 6 for Fig E1, A and B; n = 2 for mRNA and n = 1 for protein in Fig E1, C). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

9 Fig E2 Network diagram of genes depicting pathways involved in activation of TH2 cells induced by PGD2 and LTE4 based on microarray data. A, PI3K pathway. B, Apoptosis pathway. Red color shows gene upregulation, and green color shows downregulation. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

10 Fig E3 Phosphorylation of Akt in TH2 cells after treatment with PGD2 and LTE4 in the presence or absence of TM30089 and montelukast. The intensity of the bands for phospho-Akt was quantified after normalization with the bands for total Akt. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

11 Fig E4 Effect of TM30089 and montelukast on transcriptional regulation of cytokine genes induced by PGD2 and LTE4 in TH2 cells determined by using qPCR. The control sample was treated as 1-fold (n = 1). Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

12 Fig E5 Effect of IL-8 on neutrophil migration. A, Neutrophil migration to various concentrations of rhIL-8 in chemotaxis assay. B, Effect of increasing concentration of anti–IL-8 antibody on neutrophil migration induced by 50 nmol/L rhIL-8. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

13 Fig E6 Effect of GM-CSF on the decrease in CD16 levels in neutrophils, a biomarker of apoptosis, induced by serum deprivation. A, Decrease of CD16high neutrophils with the time of serum deprivation. B, Inhibitory effect of various concentration of rhGM-CSF on the decrease of CD16high neutrophils induced by serum deprivation for 12 hours. C, The inhibitory effect of rhGM-CSF (1 ng/mL) was reversed by anti–GM-CSF antibody in a dose-dependent manner. IC50, Inhibitory concentration of 50%. Journal of Allergy and Clinical Immunology  , e11DOI: ( /j.jaci ) Copyright © 2014 The Authors Terms and Conditions

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