Critical link between TRAIL and CCL20 for the activation of TH2 cells and the expression of allergic airway disease.
The role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in immune responses mediated by T-helper 2 (T(H)2) 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 T(H)2 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.
Weckmann
Markus
M
Department of Paediatrics and Adolescent Medicine, Albert Ludwigs University Freiburg, 79106 Freiburg, Germany.
Collison
Adam
A
Simpson
Jodie L
JL
Kopp
Matthias V
MV
Wark
Peter A B
PA
Smyth
Mark J
MJ
Yagita
Hideo
H
Matthaei
Klaus I
KI
Hansbro
Nicole
N
Whitehead
Bruce
B
Gibson
Peter G
PG
Foster
Paul S
PS
Mattes
Joerg
J
D000818:Animals; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000378:metabolism; D054418:Chemokine CCL20 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D034622:RNA Interference; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000276:immunology*
C493447:CCL20 protein, mouse; D054418:Chemokine CCL20; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse