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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,

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Presentation on theme: "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,"— Presentation transcript:

1 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, BS, Jyoti Thaikoottathil, PhD, Richard J. Martin, MD, Russell P. Bowler, MD, PhD, Hong Wei Chu, MD  Journal of Allergy and Clinical Immunology  Volume 129, Issue 3, Pages e2 (March 2012) DOI: /j.jaci Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Increased IRAK-M protein expression in airway epithelial cells from asthmatic patients. Upper panel, Airway epithelial IRAK-M protein quantitative data in endobronchial biopsy specimens of healthy subjects (n = 4) and asthmatic patients (n = 6). Lower panel, Representative IRAK-M immunohistochemistry staining in bronchial epithelial cells and submucosal inflammatory cells (black arrows, original magnification ×200). Data are presented as means (thick horizontal lines) ± SEMs. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 IL-13 induces IRAK-M protein expression in cultured human brushed bronchial epithelial cells. Upper panel, IRAK-M protein quantitative data (means ± SEM) in healthy subjects (n = 4) and asthmatic patients (n = 6). Lower panel, Representative IRAK-M and GAPDH Western blots. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 PI3K activation is required for IL-13–induced IRAK-M expression. A, Representative phospho-Akt (pAkt) and total Akt Western blots (n = 3 independent experiments). B, Upper level, IRAK-M protein quantitative data (means ± SEMs) are from 4 independent experiments. Lower panel, Representative IRAK-M and GAPDH Western blots. DMSO, Dimethyl sulfoxide; Wort, wortmannin. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 c-Jun directly binds to the IRAK-M gene promoter through PI3K activation on IL-13 stimulation. A, Representative phospho–c-Jun and GAPDH Western blots (n = 4 independent experiments). B, Phospho–c-Jun activity data (means ± SEM) are from 3 independent experiments. C, Chromatin immunoprecipitation assay. Left panel, Increased c-Jun binding to IRAK-M gene promoter after IL-13. Data (means ± SEM) are from 3 independent experiments. Right panel, Representative agarose gel electrophoresis. Ab, Antibody; DMSO, dimethyl sulfoxide; Wort, wortmannin. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 IL-13 decreases TLR2 protein expression in human airway epithelial cells. A, TLR2 protein quantitative data in cultured brushed bronchial epithelial cells from healthy subjects (n = 4) and asthmatic patients (n = 6). B, PI3K inhibition restored TLR2 protein expression in IL-13–treated normal human tracheobronchial epithelial cells (n = 4). Data are presented as means ± SEMs. DMSO, Dimethyl sulfoxide; Wort, wortmannin. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Role of IRAK-M in IL-13–mediated impairment of epithelial TLR2 signaling. A, IRAK-M shRNA (shIRAK-M) significantly reduced IRAK-M mRNA (left panel) and protein (right panel) expression compared with the control (firefly luciferase shRNA [shLUC]) in normal human brushed bronchial epithelial cells (n = 4). B, NF-κB p65 activity, TLR2 protein, and human hBD2 peptide levels in normal human brushed bronchial epithelial cells that were transduced with shLUC or shIRAK-M, followed by IL-13, Pam2CSK4 (Pam2), or both treatments (n = 4). Short thick horizontal lines represent means. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 IRAK-M overexpression decreases TLR2 signaling activation in NCI-H292 cells. A, Overexpression of human IRAK-M protein was confirmed by using Western blotting. B, NF-κB p65 activity. C, IL-8 protein levels in cell supernatants. Data are from 3 independent experiments and presented as means ± SEMs. EV, Empty vector; hIRAK-MV, human IRAK-M vector. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig 8 IL-4 induces IRAK-M protein expression in cultured normal human tracheobronchial epithelial cells. Representative IRAK-M and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) Western blots of 4 replicates are shown. Journal of Allergy and Clinical Immunology  , e2DOI: ( /j.jaci ) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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