IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7–mediated Fas ligand cleavage from bronchial epithelial cells Samuel J. Wadsworth,

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Presentation transcript:

IL-13 and TH2 cytokine exposure triggers matrix metalloproteinase 7–mediated Fas ligand cleavage from bronchial epithelial cells Samuel J. Wadsworth, PhD, Ryo Atsuta, MD, PhD, J. Oliver McIntyre, PhD, Tillie-Louise Hackett, PhD, Gurpreet K. Singhera, PhD, Delbert R. Dorscheid, MD, PhD Journal of Allergy and Clinical Immunology Volume 126, Issue 2, Pages 366-374.e8 (August 2010) DOI: 10.1016/j.jaci.2010.05.015 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 MMP-7 expression in normal (A and C) and asthmatic (B and D) airway epithelial tissue. Fig 1, A, In healthy subjects MMP-7 (pink) is present in ciliated cells (arrows). Fig 1, B, Patients with severe asthma express MMP-7 throughout the epithelium, including basal cells (arrows). Fig 1, C and D, Isotype controls for normal and asthmatic tissue, respectively. E, Cell-specific MMP-7 positivity per millimeter of basement membrane. ∗∗P < .01 and ∗∗∗P < .001, ANOVA (n = 5). NS, Not significant. F, ISZ with PB-M7VIS showing a cleaved FITC signal (arrows, goblet cells). Scale bars = 25 μm. Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TH2 cytokines increase MMP-3/MMP-7 expression and activity in 1HAEo− cells. A and B, MMP-3 (Fig 2, A) and MMP-7 (Fig 2, B) mRNA expression levels measured by means of real-time PCR (n = 7). C and D, MMP-3 (Fig 2, C) and MMP-7 (Fig 2, D) activity in cell supernatants measured by means of casein zymography (n = 4-5). ∗∗P < .01 and ∗P < .05 versus untreated control, ANOVA. Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 TH2 cytokines cause sFasL release and a transient increase in mFasL presentation. A, Western blots showing MMP-3 and MMP-7 expression in 1HAEo− and 16HBE14o− cells. B, sFasL ELISA of supernatants from cytokine-treated 1HAEo− cells. ∗∗P < .01 versus untreated control, ANOVA (n = 3). C, mFasL expression on cytokine-treated 1HAEo− cells, as determined by means of FACS analysis. ∗P < .05, Student t test (n = 5-8). Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TH2 cytokines trigger MMP-7/FasL colocalization. A, Confocal images of 1HAEo− cells from 0 (untreated) to 24 hours after cytokine treatment stained for MMP-7 (green), FasL (red), nuclei (blue), and a 3-dimensional merged image (M). B, Yellow MMP-7/FasL colocalization signal was quantified by using Pearson correlation values. ∗∗P < .01 versus untreated control, ANOVA (n = 3-7 fields). Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Recombinant MMP-7 causes AEC sFasL release and reduces cell-surface mFasL levels. A, sFasL ELISA of 1HAEo− supernatants after 6 hours of incubation with rhMMP-7. B, Time course of sFasL release with 1 μg/mL rhMMP-7. ∗∗P < .01 versus untreated controls, ANOVA (n = 3-4). C, FACS shows that 4 hours of rhMMP-7 treatment reduces 1HAEo− cell mFasL levels. ∗P < .05 versus untreated control, ANOVA (n = 4). Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 siRNA knockdown of MMP-7 inhibits mFasL cleavage. A, Casein zymograms demonstrate proteolytic activity in 1HAEo− supernatants corresponding to the major band in MMP-7–stained cell lysate (i). Fig 6, A (ii), and B, Transfection with MMP7–specific siRNA reduced MMP-7 activity compared with that seen in scrambled siRNA-transfected controls. C, FACS to show mFasL expression in MMP7 siRNA and scrambled siRNA-transfected 1HAEo− cells 16 hours after cytokine treatment. ∗P < .05, ANOVA (n = 7). Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fluorescence ISZ demonstrates airway epithelial MMP-7 activity Fluorescence ISZ demonstrates airway epithelial MMP-7 activity. A and B, Airway epithelium stained with DAPI and hematoxylin and eosin (H&E), respectively. C, Airway sections incubated with PB-M7VIS substrate demonstrate substrate cleavage in the epithelium (arrows) by means of FITC signal at 2 hours. D, TRITC reference. E, Epithelial FITC/TRITC ratio was quantified at several time points. F, A fluorescent plate assay using rhMMP-7 and PB-M7VIS shows similar FITC/TRITC kinetics to tissue, with no change in negative controls. Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

1HAEo− cell mFasL expression by means of FACS analysis and FasL mRNA quantification after cytokine addition. A, mFasL FACS traces of 1HAEo− cells 4 hours after cytokine treatment. B, Postcytokine FasL mRNA expression determined by means of real-time PCR. ∗P < .05 and ∗∗P < .01 versus untreated control, ANOVA (n = 3). Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Recombinant MMP-7 causes sFasL release from primary HBECs Recombinant MMP-7 causes sFasL release from primary HBECs. A, sFasL ELISA of supernatants from primary HBECs after 6 hours of incubation with rhMMP-7. B, MMP-7 (1 μg/mL) causes rapid sFasL release. ∗∗P < .01 versus untreated controls, ANOVA (n = 3-4). Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

MMP -7 siRNA inhibits mFasL cleavage after cytokine treatment MMP -7 siRNA inhibits mFasL cleavage after cytokine treatment. FACS traces show mFasL expression by 1HAEo− cells transfected with 100 nmol/L MMP-7 or scrambled siRNA 16 hour after cytokine treatment. Journal of Allergy and Clinical Immunology 2010 126, 366-374.e8DOI: (10.1016/j.jaci.2010.05.015) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions