Article abstract
Nature Medicine 13, 1308 - 1315 (2007)
Published online: 14 October 2007 | doi:10.1038/nm1660
Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease
Markus Weckmann1, Adam Collison2, Jodie L Simpson2,3, Matthias V Kopp1, Peter A B Wark2,3, Mark J Smyth4, Hideo Yagita5, Klaus I Matthaei6, Nicole Hansbro2, Bruce Whitehead7, Peter G Gibson2,3, Paul S Foster2,6 & Joerg Mattes1,2,7
Abstract
The role of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (TH2) lymphocytes is unknown. Here we characterize the development of allergic airway disease in TRAIL-deficient (Tnfsf10-/-) mice and in mice exposed to short interfering RNA targeting TRAIL. We show that TRAIL is abundantly expressed in the airway epithelium of allergic mice and that inhibition of signaling impairs production of the chemokine CCL20 and homing of myeloid dendritic cells and T cells expressing CCR6 and CD4 to the airways. Attenuated homing limits TH2 cytokine release, inflammation, airway hyperreactivity and expression of the transcriptional activator STAT6. Activation of STAT6 by interleukin-13 restores airway hyperreactivity in Tnfsf10-/- mice. Recombinant TRAIL induces pathognomic features of asthma and stimulates the production of CCL20 in primary human bronchial epithelium cells. TRAIL is also increased in sputum of asthmatics. The function of TRAIL in the airway epithelium identifies this molecule as a target for the treatment of asthma.
- Department of Paediatrics and Adolescent Medicine, Albert Ludwigs University Freiburg, 79106 Freiburg, Germany.
- Centre for Asthma and Respiratory Diseases (CARD), School of Biomedical Science, Faculty of Health, University of Newcastle and Hunter Medical Research Institute, Newcastle 2301, Australia.
- Department of Respiratory and Sleep Medicine, Hunter Medical Research Institute, Newcastle 2305, New South Wales, Australia.
- Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne 3002, Australia.
- Department of Immunology, Juntendo University School of Medicine, 113-8421 Tokyo, Japan.
- Division of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra 2601, Australia.
- Paediatric Respiratory and Sleep Medicine, Department of Paediatrics, John Hunter Children's Hospital, Newcastle 2305, Australia.
Correspondence to: Joerg Mattes1,2,7 e-mail: joerg.mattes@newcastle.edu.au
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