IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids Carine Blanchard, PhD, Melissa K. Mingler,

Slides:

Advertisements

Similar presentations

Maria B. Sukkar, PhD, Shaoping Xie, PhD, Nadia M

Advertisements

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

Russell S. Traister, MD, PhD, Crystal E. Uvalle, BS, Gregory A

Asthma inflammatory phenotypes show differential microRNA expression in sputum Tania Maes, PhD, Francisco Avila Cobos, MSc, Florence Schleich, MD, PhD,

Transcriptome analysis of proton pump inhibitor–responsive esophageal eosinophilia reveals proton pump inhibitor–reversible allergic inflammation Ting.

Modulation by aspirin of nuclear phospho–signal transducer and activator of transcription 6 expression: Possible role in therapeutic benefit associated.

Ryan H. Dougherty, MD, Sukhvinder S

Regulation of GM-CSF expression by the transcription factor c-Maf

Reduced IFN-γ receptor expression and attenuated IFN-γ response by dendritic cells in patients with atopic dermatitis Eva Gros, MSc, Susanne Petzold,

MicroRNA signature in patients with eosinophilic esophagitis, reversibility with glucocorticoids, and assessment as disease biomarkers Thomas X. Lu,

IL-32 is expressed by human primary keratinocytes and modulates keratinocyte apoptosis in atopic dermatitis Norbert Meyer, MD, Maya Zimmermann, PhD,

Histologic eosinophilic gastritis is a systemic disorder associated with blood and extragastric eosinophilia, TH2 immunity, and a unique gastric transcriptome

Identification of novel gene signatures in patients with atopic dermatitis complicated by eczema herpeticum Lianghua Bin, MD, PhD, Michael G. Edwards,

Julie M. Caldwell, PhD, Carine Blanchard, PhD, Margaret H

Inflammatory marker analysis in psoriatic skin under topical phosphodiesterase 4 inhibitor treatment Lennart M. Roesner, PhD, Petra Kienlin, Gabriele.

FcεRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells Shigeru Okumura, DDS, PhD, Hironori Sagara,

The proteome of Toll-like receptor 3–stimulated human immortalized fibroblasts: Implications for susceptibility to herpes simplex virus encephalitis

Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease Alex Poole, MS, Cydney Urbanek, BS, Celeste Eng, BS, Jeoffrey.

D prostanoid receptor 2 (chemoattractant receptor–homologous molecule expressed on TH2 cells) protein expression in asthmatic patients and its effects.

Mark Rochman, PhD, Jared Travers, BS, Cora E. Miracle, Mary C

Pediatric Eosinophilic Esophagitis Symptom Scores (PEESS v2

Dawn C. Newcomb, PhD, Madison G

The anti-inflammatory effect of glucocorticoids is mediated by glucocorticoid-induced leucine zipper in epithelial cells Jane Eddleston, PhD, Jack Herschbach,

A critical role for IL-18 in transformation and maturation of naive eosinophils to pathogenic eosinophils Sathisha Upparahalli Venkateshaiah, PhD, Akanksha.

Clara cell 16-kd protein downregulates TH2 differentiation of human naive neonatal T cells Sofi Johansson, MSc, Göran Wennergren, MD, PhD, Nils Åberg,

The innate antiviral response upregulates IL-13 receptor α2 in bronchial fibroblasts Gemma Campbell-Harding, PhD, Hannah Sawkins, BSc, Nicole Bedke, PhD,

Carol J. Henderson, PhD, RD, J. Pablo Abonia, MD, Eileen C

CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis Esther Morel, PhD, Salvador Escamochero,

Airway epithelial cells from asthmatic children differentially express proremodeling factors Jesus M. Lopez-Guisa, PhD, Claire Powers, BA, Daniele File,

Merritt L. Fajt, MD, Stacy L

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages Elena Goleva, PhD, Pia J. Hauk, MD, Clifton.

IL-2–inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells Arun K. Kannan, MS, Nisebita.

T-box 21 transcription factor is responsible for distorted TH2 differentiation in human peripheral CD4+ T cells Osamu Kaminuma, DVM, PhD, Fujiko Kitamura,

Profiling of human CD4+ T-cell subsets identifies the TH2-specific noncoding RNA GATA3-AS1 Huan Zhang, MD, PhD, Colm E. Nestor, PhD, Shuli Zhao, PhD,

Carine Blanchard, PhD, Emily M

Cigarette smoke combined with Toll-like receptor 3 signaling triggers exaggerated epithelial regulated upon activation, normal T-cell expressed and secreted/CCL5.

Inhibition of angiogenesis by IL-32: Possible role in asthma

Antiviral activity of human β-defensin 3 against vaccinia virus

Role of hyaluronan and hyaluronan-binding proteins in human asthma

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations Giovanna.

Downregulation of a disintegrin and metalloproteinase 33 by IFN-γ in human airway smooth muscle cells Isao Ito, MD, PhD, Johanne D. Laporte, PhD, Pierre.

Streptococcus pyogenes–induced cutaneous lymphocyte antigen–positive T cell– dependent epidermal cell activation triggers TH17 responses in patients with.

The Editors' Choice Journal of Allergy and Clinical Immunology

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

Staphylococcal exotoxins are strong inducers of IL-22: A potential role in atopic dermatitis Margarete Niebuhr, MD, Helena Scharonow, MS, Merle Gathmann,

Josée Lamoureux, PhD, Jana Stankova, PhD, Marek Rola-Pleszczynski, MD

J. Pablo Abonia, MD, Ting Wen, PhD, Emily M

IL-17E upregulates the expression of proinflammatory cytokines in lung fibroblasts Séverine Létuvé, PhD, Stéphane Lajoie-Kadoch, MSc, Séverine Audusseau,

Joseph D. Sherrill, PhD, Pei-Song Gao, MD, PhD, Emily M

Live and heat-treated probiotics differently modulate IL10 mRNA stabilization and microRNA expression Audrey Demont, BS, Feriel Hacini-Rachinel, PhD,

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

Correlation between CCL26 production by human bronchial epithelial cells and airway eosinophils: Involvement in patients with severe eosinophilic asthma

Jenny Seltmann, PhD, Lennart M

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Heterozygous N-terminal deletion of IκBα results in functional nuclear factor κB haploinsufficiency, ectodermal dysplasia, and immune deficiency Douglas.

Claudin-1 expression in airway smooth muscle exacerbates airway remodeling in asthmatic subjects Hiroyuki Fujita, MD, PhD, Maciej Chalubinski, MD, PhD,

Eosinophilic esophagitis: Pathogenesis, genetics, and therapy

Eosinophilic esophagitis versus proton pump inhibitor–responsive esophageal eosinophilia: Transcriptome analysis Tetsuo Shoda, MD, PhD, Akio Matsuda,

A flow cytometry–based diagnosis of eosinophilic esophagitis

Prostaglandin E2–EP3 signaling suppresses skin inflammation in murine contact hypersensitivity Tetsuya Honda, MD, PhD, Toshiyuki Matsuoka, MD, PhD, Mayumi.

Charles W. DeBrosse, MD, Margaret H. Collins, MD, Bridget K

PGD2 induces eotaxin-3 via PPARγ from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis Kyoko Nakahigashi, MD, Hiromi Doi, MS,

Bleomycin hydrolase downregulation in lesional skin of adult atopic dermatitis patients is independent of FLG gene mutations Laurence Pellerin, PhD,

Long-term outcomes in pediatric-onset esophageal eosinophilia

IL-31 is associated with cutaneous lymphocyte antigen–positive skin homing T cells in patients with atopic dermatitis Janine Bilsborough, PhD, Donald.

Carine Blanchard, PhD, Emily M

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Eosinophil progenitor levels are increased in patients with active pediatric eosinophilic esophagitis David W. Morris, MD, Emily M. Stucke, BA, Lisa.

IL-2–inducible T-cell kinase modulates TH2-mediated allergic airway inflammation by suppressing IFN-γ in naive CD4+ T cells Arun K. Kannan, MS, Nisebita.

Presentation transcript:

IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids Carine Blanchard, PhD, Melissa K. Mingler, MS, Maria Vicario, PhD, J. Pablo Abonia, MD, Yi Ying Wu, MS, Thomas X. Lu, BS, Margaret H. Collins, MD, Philip E. Putnam, MD, Susanne I. Wells, PhD, Marc E. Rothenberg, MD, PhD Journal of Allergy and Clinical Immunology Volume 120, Issue 6, Pages 1292-1300 (December 2007) DOI: 10.1016/j.jaci.2007.10.024 Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-13 and IL-4 mRNA expression in biopsy samples from healthy (NL) subjects and patients with EE. The expression of IL-13 (A) and IL-4 (B) is shown. Each mRNA value is normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA expression from the same sample and is expressed as a fold increase. The black lines represent the mean value in each group. P values were calculated by using the Mann-Whitney U test (2 groups; n = 8-9 and 13-21 subjects for the healthy and EE groups, respectively). Journal of Allergy and Clinical Immunology 2007 120, 1292-1300DOI: (10.1016/j.jaci.2007.10.024) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Gene expression analysis in primary esophageal cells after IL-13 stimulation and comparison with the EE transcript signature. A, The 54,765 genes of the HG-U133 chip were subjected to fold-change filter in patients with EE versus healthy subjects and IL-13–stimulated primary cell cultures versus unstimulated cells. Spearman correlation and linear regression were calculated. B, The list displays 33 transcripts that were upregulated 5-fold or greater and 5 transcripts that were downregulated 4-fold or greater compared with unstimulated cells. C, The genes modified by 1.5-fold or greater on average in IL-13–stimulated cells (100 ng/mL) are presented in a heat diagram in 3 primary-culture patient biopsy specimens (1, 2, and 3), unstimulated and stimulated. Upregulated genes are shown in red, and downregulated genes are shown in blue. The magnitude of the gene changes is proportional to the darkness of the color. D, The fold increase of eotaxin-3 mRNA expression compared with the untreated value was quantified by means of real-time PCR. E, Eotaxin-3 released in the culture supernatant is expressed in nanograms per milliliter. Results are presented as means ± range and are representative of experiments performed in 5 different patients. Journal of Allergy and Clinical Immunology 2007 120, 1292-1300DOI: (10.1016/j.jaci.2007.10.024) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 IL-13 receptor chain expression in esophageal cells and eotaxin-3 production by esophageal cell lines after IL-13 stimulation. A, The TE-1, TE-6, TE-7, and TE-13 esophageal cell lines were subjected to PCR analysis for IL-4Rα, IL-13Rα1, IL-13Rα2, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA expression. B, Flow cytometric analysis of IL-4R, IL-13Rα1, and IL-13Rα2 chain expression in the TE-7 cell line (dark lines). Controls were performed with an irrelevant IgG1 (gray lines). C, The TE-1, TE-6, TE-7, and TE-13 esophageal cell lines were stimulated for 24 hours with IL-13 (0, 1, 10, and 100 ng/mL). The fold increase of eotaxin-3 mRNA expression compared with that of the untreated cells is shown. D and E, TE-7 cells were cultured with IL-13 (0, 1, 10, and 100 ng/mL) for 1, 6, 12, 24, and 48 hours. Eotaxin-3 protein released in the culture supernatant was quantified by means of ELISA. Results are presented as means ± range and are representative of at least 3 experiments performed in triplicate. Journal of Allergy and Clinical Immunology 2007 120, 1292-1300DOI: (10.1016/j.jaci.2007.10.024) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Human eotaxin-3 promoter activity after IL-13 stimulation and the role of STAT6. A, TE-7 cells were transfected with pGL3 basic containing the eotaxin-3 promoter (P800) and phRLTK. Cells were stimulated with IL-13 (0, 1, 10, and 100 ng/mL) B, TE-7 cells were transfected with pGL3 basic containing different lengths of the eotaxin-3 promoter (P800, P500, and P100) and promoters containing mutations in the STAT6-responsive elements (MUT1, MUT2, and MUT1&2). C, The TE-7 cells were cotransfected with P800 and a dominant-negative form of STAT6 (DNSTAT6) or the empty vector (EV). D, TE-7 cells were cotransfected with P800 and the expression vector containing STAT6:ER. The cells were stimulated with 4-hydroxytamoxifene (4HT; 10 μmol/L). Results are presented as the ratio of the luciferase firefly/Renilla activities. E, Esophageal keratinocytes (TE-7) were pretreated with IL-13 (0 or 100 ng/mL) and actinomycin D (Actino; 0 or 10 μmol/L) for 0 to 48 hours. Results are presented as a percentage of eotaxin-3 mRNA compared with time 0 hours (100%; black and gray dashed lines for media and IL-13, respectively). Trend lines (black and gray lines for media and IL-13, respectively) were calculated. Journal of Allergy and Clinical Immunology 2007 120, 1292-1300DOI: (10.1016/j.jaci.2007.10.024) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effect of glucocorticoids on the EE transcriptome and resistant genes. A and B, The expression of IL-13 (Fig 5, A) and eotaxin-3 (Fig 5, B) mRNA is shown in healthy subjects (NL), patients with EE, and patients with EE treated successfully with FP (n = 8-9, 13-19, and 6-8 subjects for the NL, EE, and FP groups, respectively). C, Total mRNA was subjected to microarray analysis. Upregulated genes are shown in red, and downregulated genes are shown in blue. Each column represents a separate patient (NL, EE, and FP Rx), and each line represents a gene. D, Genes that are resistant to glucocorticoid therapy are shown with their Affymetrix accession numbers and their fold change in patients with EE and in treated patients with EE. E, Expression of cadherin-26 (CDH26) was quantified by means of real-time PCR. Each data point corresponds to a separate individual (n = 9, 11, and 7 subjects for the NL, EE, and FP groups, respectively). P values were calculated using Kruskal-Wallis tests (3 groups). Journal of Allergy and Clinical Immunology 2007 120, 1292-1300DOI: (10.1016/j.jaci.2007.10.024) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions