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Autocrine-regulated airway smooth muscle cell migration is dependent on IL-17–induced growth-related oncogenes  Laila A. Al-Alwan, PhD, Ying Chang, PhD,

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Presentation on theme: "Autocrine-regulated airway smooth muscle cell migration is dependent on IL-17–induced growth-related oncogenes  Laila A. Al-Alwan, PhD, Ying Chang, PhD,"— Presentation transcript:

1 Autocrine-regulated airway smooth muscle cell migration is dependent on IL-17–induced growth-related oncogenes  Laila A. Al-Alwan, PhD, Ying Chang, PhD, Carolyn J. Baglole, PhD, Paul-André Risse, PhD, Andrew J. Halayko, PhD, James G. Martin, MD, David H. Eidelman, MD, PhD, Qutayba Hamid, MD, PhD  Journal of Allergy and Clinical Immunology  Volume 130, Issue 4, Pages e6 (October 2012) DOI: /j.jaci Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 IL-17/ASMC–induced supernatants promote ASM migration. IL-17A/ASMC– or IL-17F/ASMC–induced supernatants were used to investigate ASMC migration. ASMC migration was significant with IL-17A–induced (A) and IL-17F–induced (B) supernatants. N  ≥ 7 independent experiments using ASMCs from 5 subjects. *P < .05, **P < .01, and ***P < .001 compared with nonstimulated control supernatants. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 IL-17 induces dose-dependent production of GRO-α, GRO-β, and GRO-γ from ASMCs. GRO production in supernatants was investigated by means of ELISA. GRO-α (A), GRO-β (B), and GRO-γ (C) expression increased significantly after IL-17A, IL-17F, and IL-17A/IL-17F stimulation. N = 7 independent experiments using ASMCs from 7 subjects. *P < .05, **P < .01, and ***P < .001 compared with nonstimulated control supernatants. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 IL-17 induces GRO expression in ASMCs. GRO mRNA expression was assessed by means of quantitative PCR. IL-17 stimulation increased GRO-α (A), GRO-β (B), and GRO-γ (C) expression significantly. N = 4 independent experiments. *P < .05, **P < .01, and ***P < .001 compared with nonstimulated controls. $P < .05 and $$P < .01 compared between time points of similar conditions. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 MAPK pathway activation by IL-17–related cytokines. A and B, Western blot quantification of IL-17A– and IL-17F–induced ERK1/2 (Fig 4, A) and p38 (Fig 4, B) activation represented by an increase in phosphorylated ERK1/2 and p38 signals. C, Efficacy of the pharmacologic inhibitors PD and BIRB0796 in reducing the phosphorylation of ERK1/2 and p38 MAPKs, respectively. N = 3 independent experiments. *P < .05, **P < .01, and ***P < .001 compared with nonstimulated controls. $P < .05, $$P < .01, and $$$P < .001 compared between conditions. Results are expressed as means ± SEMs. DMSO, Dimethyl sulfoxide. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 GRO production is dependent on the ERK1/2 MAPK pathway. ELISA quantification of GRO production in IL-17/ASMC–induced supernatants after pharmacologic inhibitor treatment. GRO-α (A), GRO-β (B), and GRO-γ (C) production was reduced significantly after ERK1/2 MAPK pathway inhibition. N = 5 independent experiments. **P < .01 and ***P < .001 compared with IL-17–stimulated supernatants. Results are expressed as means ± SEMs. BIRB, BIRB0796; PD, PD Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 ASMC migration induced by IL-17/ASMC–derived supernatants is GRO mediated. IL-17/ASMC–derived supernatants after neutralization of GRO activity were used to investigate ASMC migration. Neutralizing GRO activity in supernatants significantly abolished ASMC migration. *P < .05 and ***P < .001 compared with isotype control. N = 5 independent experiments using ASMCs from 4 subjects. Results are expressed as means ± SEMs. Ab, Antibody. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 Fig 7 GROs promote ASMC migration through the CXCR2 receptor. Increasing concentrations of GROs were used to investigate ASMC migration. A, GROs induce significant migration of ASMCs. B, GRO-induced migration of ASMCs from asthmatic patients is comparable with that seen in normal ASMCs. C, CXCR2 antagonist attenuated GRO-induced ASMC migration. Platelet-derived growth factor β subunit B (PDGF-BB; 10 ng/mL) is the positive control. N ≥ 4 independent experiments. *P < .05, **P < .01, and ***P < .001 compared with control media; $$P < .01 compared between conditions. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fig 8 IL-1β/ASMC– and TNF-α/ASMC–induced supernatants have no effect on ASMC migration. IL-1β–induced (A) or TNF-α–induced (B) supernatants did not induce ASMC migration. N ≥ 6 independent experiments using ASMCs from 5 subjects. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 Fig E1 GRO chemokine production induced by IL-17A and IL-17F stimulation to human ASMCs. Serum-starved ASMCs were treated with or without (20 ng/mL) IL-17A or IL-17F for 24 hours. The supernatants were analyzed for chemokine production by using a membrane-based chemokine antibody array. There was an approximately 2-fold increase in GRO production after treatment with IL-17A and IL-17F. BLC, B lymphocyte chemoattractant; CTACK, cutaneous T-cell-attracting chemokine; ENA-78, neutrophil-activating peptide 78; MIG, monokine induced by gamma interferon; MIP, macrophage inflammatory protein; MPIF-1, myeloid progenitor inhibitory factor 1; NAP2, neutrophil-activating protein 2; TARC, thymus and activation regulated chemokine; TECK, thymus-expressed chemokine. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Fig E2 IL-17 induces continuous GRO production from human ASMCs. IL-17–induced GRO-α (A) and GRO-β (B) production was maintained throughout the stimulation course, whereas GRO-γ (C) production was time dependent. N = 4 independent experiments. *P < .05, **P < .01, and ***P < .001 compared with nonstimulated controls. $$P < .01 compared between time points of similar conditions. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 Fig E3 IL-17 induces production of GRO-α, GRO-β, and GRO-γ from ASMCs of asthmatic patients. GRO production in supernatants was investigated by using ELISA. GRO-α, GRO-β, and GRO-γ expression increased significantly after IL-17A (A) and IL-17F (B) stimulation. N = 3 independent experiments using ASMCs from 3 subjects. *P < .05, **P < .01, and ***P < .001 compared with nonstimulated control supernatants. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Fig E4 Residual IL-17A and IL-17F in IL-17/ASMC–derived supernatants have no effect on ASMC migration. ASMC migration induced by IL-17A–induced (A) or IL-17F–stimulated (B) supernatants was not affected after treatment with anti–IL-17A or anti–IL-17F, respectively. N = 3 independent experiments using ASMCs from 3 subjects. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

14 Fig E5 IL-1β and TNF-α stimulation induces GRO production from ASMCs. GRO production in supernatants was investigated by using ELISA. GRO-α, GRO-β, and GRO-γ expression increased significantly after IL-1β (A) and TNF-α (B) stimulation. N = 4 independent experiments using ASMCs from 4 subjects. **P < .01 and ***P < .001 compared with nonstimulated control supernatants. Results are expressed as means ± SEMs. Journal of Allergy and Clinical Immunology  , e6DOI: ( /j.jaci ) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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