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Interleukin-13 Mediates a Fundamental Pathway for Airway Epithelial Mucus Induced by CD4 T Cells and Interleukin-9

Sections of Pulmonary and Critical Care Medicine and Immunobiology, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut; Howard Hughes Medical Institute, New Haven, Connecticut; Department of Medicine, Pulmonary Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Pathology and Laboratory Medicine Service, V. A. Connecticut Health Care System, West Haven, Connecticut

Address correspondence to: Lauren Cohn, M.D., Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208057, New Haven, CT 06520-8057. E-mail: lauren.cohn{at}yale.edu

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-4R 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-B, 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.

Abbreviations: antigen-presenting cells, APC • bronchoalveolar lavage, BAL • enzyme-linked immunosorbent assay, ELISA • fluorescence-activated cell sorter, FACS • fluorescence in situ hybridization, FISH • histologic mucus index, HMI • interferon, IFN • interleukin, IL • nuclear factor-B, NF-B • ovalbumin, OVA • periodic acid Schiff, PAS • phosphate-buffered saline, PBS • peripheral blood mononuclear cells, PBMC • OVA peptide ^323–339, pOVA^323–339 • reverse transcription–polymerase chain reaction, RT-PCR • T cell receptor, TCR • transgenic, Tg

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