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TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis  Maya Zimmermann, PhD, Andrea Koreck, MD, Norbert.

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Presentation on theme: "TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis  Maya Zimmermann, PhD, Andrea Koreck, MD, Norbert."— Presentation transcript:

1 TNF-like weak inducer of apoptosis (TWEAK) and TNF-α cooperate in the induction of keratinocyte apoptosis  Maya Zimmermann, PhD, Andrea Koreck, MD, Norbert Meyer, MD, Tomasz Basinski, PhD, Flurina Meiler, PhD, Burgler Simone, PhD, Stefan Woehrl, MD, Katharina Moritz, MD, Thomas Eiwegger, MD, Peter Schmid-Grendelmeier, MD, Lajos Kemeny, MD, Cezmi A. Akdis, MD  Journal of Allergy and Clinical Immunology  Volume 127, Issue 1, Pages e10 (January 2011) DOI: /j.jaci Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 Fig 1 The TNF-α and TWEAK combination induces keratinocyte (KC) apoptosis. Keratinocytes were stimulated with 10 ng/mL TNF-α and 100 ng/mL TWEAK. A and B, Kinetic cell death of 2 independent experiments (mean ± SD) in primary healthy (Fig 1, A) and transformed (Fig 1, B) keratinocytes. C and D, Annexin V and 7-AAD staining of healthy, AD, and psoriatic keratinocytes 4 days after stimulation with cytokines (n = 5 for each group). Fig 1, D, indicates 1 representative experiment (mean ± SD). Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 Fig 2 The TNF-α and TWEAK combination induces apoptosis in artificial skin equivalents. Artificial skin equivalents were cultured with 10 ng/mL TNF-α and 100 ng/mL TWEAK for 5 days. Positive cells were detected by means of TUNEL. One representative example is shown of 2 independent experiments. DAPI, 4′,6-Diamidino-2-phenylindole; u.s., unstimulated. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 Fig 3 Fn14 and TNFR1 are expressed on keratinocytes and not regulated by TNF-α and TWEAK, as shown by means of quantitative real-time PCR (A; data shown represent means ± SDs, n = 3 for each group), flow cytometric analysis (B), and immunohistochemistry (C). Fig 3, B and C, show 1 representative example of healthy keratinocytes of 3 independent experiments. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 Fig 4 TNF-α and TWEAK–induced cell death takes place through TNFR1 and Fn14. Keratinocytes (KC) were stimulated with 10 ng/mL TNF-α and 100 ng/mL TWEAK. A, Anti-TNFR1 mAb, but not anti-TNFR2 mAb, blocked TNF-α and TWEAK–induced keratinocyte death. B, Induction of keratinocyte death in combination with TNF-α by anti-Fn14 mAb (ITEM-1 and ITEM-2). Fig 4, A and B, show data representing means ± SDs of 2 independent experiments. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 Fig 5 TWEAK upregulates TNF-α mRNA in healthy, AD, and psoriatic keratinocytes (A). TWEAK does not enhance TNF-α–induced TNF-α mRNA expression (F). Keratinocytes were stimulated with 100 ng/mL TWEAK (A, D, and E), 100 ng/mL TRAIL (B), 500 ng/mL mAb anti-Fas (C), and 10 ng/mL TNF-α (E and F). Means ± SDs of 3 independent experiments are shown. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 Fig 6 Fn14 is highly expressed in healthy, AD, and psoriatic skin, whereas TWEAK is highly expressed in the epidermis of AD skin but not in psoriatic and normal skin. Immunohistochemistry (IHC) and immunofluorescent (IF) staining in healthy (A), AD (B), and psoriatic (C) skin are depicted with the appropriate isotype control (i.c.). One representative example is shown (n = 3 for each group). DAPI, 4′,6-Diamidino-2-phenylindole. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 The combination of TNF-α with TRAIL or anti-Fas mAb and the combination of TWEAK and TRAIL does not enhance keratinocyte (KC) apoptosis compared with stimulation with these molecules alone in healthy, AD, and psoriatic keratinocytes. Keratinocytes were stimulated with 10 ng/mL TNF-α, 100 ng/mL TWEAK, 100 ng/mL TRAIL, and 500 ng/mL anti-Fas mAb. Data shown represent means ± SDs (n = 5 for each group). Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 Fn14, TNFR1, and TNFR2 mRNA are not regulated by TNF-α and TWEAK
Fn14, TNFR1, and TNFR2 mRNA are not regulated by TNF-α and TWEAK. Keratinocytes were stimulated with 10 ng/mL TNF-α and 100 ng/mL TWEAK. There were no differences among healthy donors, donors with AD, and donors with psoriasis (n = 3 for each group). Data shown represent means ± SDs of healthy keratinocytes. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 The simultaneous presence of TNF-α and TWEAK in cell culture induces efficient keratinocyte (KC) death. Primary keratinocytes were stimulated with 10 ng/mL TNF-α and 100 ng/mL TWEAK in the presence of 10 ng/mL cycloheximide for 48 hours. A, The mean ± SD of 3 independent experiments is shown. B, Data of 1 representative experiment are shown. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 Addition of recombinant human (rh) TWEAK to anti-TWEAK mAb significantly decreased TWEAK-positive staining to undetectable levels. TWEAK immunofluorescence staining in AD lesional skin was performed with and without adding 5 μg/mL rhTWEAK to anti-TWEAK mAb. One representative example is shown (n = 2). DAPI, 4′,6-Diamidino-2-phenylindole. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 A, TNF-α, TWEAK, TNFR1, TNFR2, and Fn14 mRNA expression in healthy control, AD, and psoriatic lesional skin biopsy specimens. Data shown represent means ± SDs (n = 5 for healthy, n = 8 for AD, and n = 6 for psoriatic skin biopsy specimens). B, TNF-α is upregulated in AD and psoriatic lesional skin compared with that seen in healthy control skin. Immunofluorescent (IF) staining in AD lesional, healthy control, and psoriatic lesional skin are depicted with the appropriate isotype control (i.c.). One representative example is shown (n = 2 for each group). DAPI, 4′,6-Diamidino-2-phenylindole. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

13 Serum levels of TWEAK did not show any differences among healthy subject, patients with AD, and patients with psoriasis. TWEAK serum levels were measured by means of ELISA. Blood of patients with AD and patients with psoriasis was taken during an acute exacerbation of disease. Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

14 TWEAK expression in keratinocytes
TWEAK expression in keratinocytes. A, Basal TWEAK mRNA expression in unstimulated healthy, AD, and psoriatic keratinocytes compared with basal TNF-α mRNA expression (mean ± SD, n = 3). B, TWEAK mRNA regulation in healthy, AD, and psoriatic keratinocytes (72 hours' stimulation, mean ± SD, n = 3). C-E, TWEAK (mean ± SD, n = 2), TNF-α, and TRAIL mRNA regulation (24 hours' stimulation). F, TWEAK expression in keratinocyte supernatants (mean ± SD, n = 2). Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

15 TWEAK mRNA basal expression in resting T cells does not show any differences among TH1, TH2, Treg, and TH17 cells. Data shown represent means ± SDs (n = 3 for each group). Journal of Allergy and Clinical Immunology  , e10DOI: ( /j.jaci ) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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