Interleukin-13 mediates a fundamental pathway for airway epithelial mucus induced by CD4 T cells and interleukin-9.
Mucus hyperproduction in asthma results from Th2-induced airway inflammation. Controversy exists about the precise mechanism of this Th2 effect. Although we showed that mucus can be induced by Th2 cells in the absence of interleukin (IL)-4, IL-5, eosinophils, and mast cells, but not without IL-4Ralpha signaling, others demonstrated that IL-4 and IL-9 can directly stimulate airway epithelial mucus. Using a system in which in vitro-generated T cell receptor transgenic Th2 cells are transferred into recipient mice and activated in the respiratory tract with inhaled antigen, we now show that CD4 Th cells can stimulate mucus only through a common, IL-13-mediated pathway. All Th cytokines depend on IL-13 for this effect and IL-13 acts, not through intermediate inflammatory cells, but on structural cells within the lung, likely the airway epithelium itself. The potency of IL-13 is shown, requiring its complete blockade for a significant reduction in mucus production. We show that mucus induction by Th2 cells does not require nuclear factor-kappaB, unlike mucins induced by gram-negative infection. These studies define in vivo pathways that lead to mucus induction and indicate that, whereas IL-13 mediates a dominant pathway for CD4 Th induced inflammation, other inflammatory stimuli activate the epithelium to produce mucus by different pathways.
Whittaker
Laurie
L
Section of Pulmonary and Critical Care Medicine, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Niu
Naiqian
N
Temann
U-Angela
UA
Stoddard
Amy
A
Flavell
Richard A
RA
Ray
Anuradha
A
Homer
Robert J
RJ
Cohn
Lauren
L
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016906:Interleukin-9 / Q000378:metabolism*; D008168:Lung / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D055271:Mucin 5AC; D009077:Mucins / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D017471:Receptors, Interferon / Q000235:genetics / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D018418:Th2 Cells / Q000378:metabolism; D000096743:Interferon gamma Receptor
D007371:Interferon-gamma; D018793:Interleukin-13; D016906:Interleukin-9; D055271:Mucin 5AC; D009077:Mucins; D016328:NF-kappa B; D017471:Receptors, Interferon; D019948:Receptors, Interleukin-4; D011994:Recombinant Proteins; D000096743:Interferon gamma Receptor; C524679:Muc5ac protein, mouse