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Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma  Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,

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Presentation on theme: "Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma  Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD,"— Presentation transcript:

1 Corticosteroid insensitivity of chemokine expression in airway smooth muscle of patients with severe asthma  Po-Jui Chang, MD, Pankaj K. Bhavsar, PhD, Charalambos Michaeloudes, PhD, Nadia Khorasani, BSc, Kian Fan Chung, MD, DSc  Journal of Allergy and Clinical Immunology  Volume 130, Issue 4, Pages e5 (October 2012) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 Cytokine-induced protein release and mRNA expression of inflammatory chemokines in ASMCs of nonasthmatic subjects and patients with nonsevere and severe asthma. After exposure to cytokines for 24 hours, CCL11 (A and B), CXCL8 (C and D), and CX3CL1 (E and F) expression was assessed by using ELISA and qRT-PCR. Horizontal lines represent medians. US, Unstimulated. #P < .05, ##P < .01, and ###P < .001 versus unstimulated. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 Comparison of cytokine-induced recruitment of p65 to promoters of inflammatory genes in ASMCs of nonasthmatic subjects and patients with nonsevere and severe asthma. ASMCs were stimulated with TNF-α or with a combination of TNF-α and IFN-γ for 60 minutes. p65 recruitment to promoters of CCL11 (A), CXCL8 (B), and CX3CL1 (C) was assessed by using ChIP assays. Horizontal lines represent medians. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Impaired suppression of induced CCL11 by dexamethasone in patients with severe asthma. ASMCs were pretreated with dexamethasone (10−10 to 10−6 mol/L, 2 hours) and stimulated with TNF-α (10 ng/mL, 24 hours). CCL11 release (A) and mRNA expression (B-D) were assessed by means of ELISA and qRT-PCR, respectively. Points and bars represent means ± SEMs. US, Unstimulated. *P < .05 versus nonasthmatic subjects. #P < .05 versus patients with nonsevere asthma. $$$P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 Impaired suppression of induced CXCL8 release and mRNA expression by dexamethasone in ASMCs of patients with severe asthma. ASMCs were treated in an identical way as described in Fig 3. CXCL8 release (A) and mRNA expression (B-D) were assessed by means of ELISA and qRT-PCR, respectively. Points and bars represent means ± SEMs. US, Unstimulated. *P < .05 and **P < .01 versus nonasthmatic subjects. $P < .05 and $$$P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 Effect of dexamethasone on cytokine-induced CX3CL1 in ASMCs of nonasthmatic subjects and patients with nonsevere and severe asthma. ASMCs were pretreated with dexamethasone (10−10 to 10−6 mol/L, 2 hours) and stimulated with TNF-α and IFN-γ (10 ng/mL each, 24 hours). CX3CL1 release (A) and mRNA expression (B-D) were assessed by means of ELISA and RT-PCR, respectively. Points and bars represent means ± SEMs. US, Unstimulated. $$P < .01 and $$$P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Comparison of induced MAPKs in ASMCs of nonasthmatic subjects and patients with nonsevere and severe asthma. ASMCs were stimulated with TNF-α (10 ng/mL) for 15 minutes. Phosphorylated and total p38 (A), JNK (B), and ERK (C) levels were assessed by means of Western blotting. Horizontal lines represent medians. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 Effect of p38α and JNK inhibitors on the suppressive effect of dexamethasone. ASMCs were pretreated with either GW or SP600125, dexamethasone, or both for 2 hours and stimulated with TNF-α for 24 hours. CCL11 (A, C, and E) and CXCL8 (B, D, and F) release were assessed by means of ELISA. Bars and points represent means ± SEMs in 4 to 6 ASMCs of patients with severe asthma. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig E1 Regulation of CCL11, CXCL8, and CX3CL1 in ASMCs. ASMCs were stimulated with TNF-α, IFN-γ, or their combination for 24 hours. CCL11 (A), CXCL8 (B), and CX3CL1 (C-F) release were assessed by means of ELISA. Bars represent means ± SEMs of 3 ASMCs of nonasthmatic subjects. *P < .05 and **P < .01 versus unstimulated. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E2 Cytokine-induced recruitment of NF-κB (p65) to promoters of inflammatory genes. ASMCs were stimulated with TNF-α or combined TNF-α and IFN-γ, as indicated. Recruitment of p65 to promoters of CCL11 (A), CXCL8 (B), and CX3CL1 (C) was assessed by using a ChIP assay. Bars represent means of 2 ASMCs from nonasthmatic subjects. CTRL, Control. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E3 Regulation of MAPKs in ASMCs. ASMCs were stimulated with TNF-α (10 ng/mL) at different time points, as indicated. Phosphorylated and total p38 (A), JNK (B), and ERK (C) levels were assessed by means of Western blotting. Bars represent means ± SEMs from 3 ASMCs of nonasthmatic subjects. *P < .05, **P < .01, and ***P < .001 versus unstimulated. Journal of Allergy and Clinical Immunology  , e5DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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