Abstract
Mice with a targeted deletion of the T-bet gene exhibit spontaneous airway hyperresponsiveness (AHR), airway inflammation, enhanced recovery of T(h)2 cytokines from bronchoalveolar lavage fluid, sub-epithelial collagen deposition and myofibroblast transformation. Here we analyze the mechanisms responsible for the chronic airway remodeling observed in these mice. CD4+ T cells isolated from the lung of T-bet-deficient mice were spontaneously activated CD44(high)CD69(high) memory T cells, with a typical T(h)2 cytokine profile. Neutralization of IL-13 but not IL-4 resulted in amelioration of AHR in airways of mice lacking T-bet. IL-13 blockade also led to reduced eosinophilia and decreased vimentin, transforming growth factor beta (TGF-beta) and alpha smooth muscle actin (alphaSMA) levels. T-bet(-/-) lung fibroblasts proliferated very rapidly and released increased amounts of TGF-beta. Interestingly, neutralization of TGF-beta ameliorated aspects of the chronic airway remodeling phenotype but did not reduce AHR. These data highlight a T-bet-directed function for IL-13 in controlling lung remodeling that is both dependent on and independent of its interaction with TGF-beta in the asthmatic airway.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Actins / metabolism
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Animals
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Asthma / etiology*
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Asthma / genetics
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Asthma / immunology
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Asthma / pathology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / pathology
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Cells, Cultured
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Cytokines / biosynthesis
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / metabolism
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Fibroblasts / immunology
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Fibroblasts / pathology
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Immunologic Memory
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Interleukin-13 / antagonists & inhibitors
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Interleukin-13 / metabolism*
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Interleukin-4 / antagonists & inhibitors
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Lung / immunology
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Lung / pathology
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Lymphocyte Activation
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Smad3 Protein
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Smad7 Protein
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T-Box Domain Proteins
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Trans-Activators / biosynthesis
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Trans-Activators / metabolism
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Transcription Factors / deficiency*
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Transcription Factors / genetics
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Transcription Factors / immunology
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Transforming Growth Factor beta / antagonists & inhibitors
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Transforming Growth Factor beta / biosynthesis
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Vimentin / metabolism
Substances
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Actins
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Cytokines
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DNA-Binding Proteins
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Interleukin-13
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Smad3 Protein
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Smad3 protein, mouse
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Smad7 Protein
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Smad7 protein, mouse
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Trans-Activators
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Transcription Factors
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Transforming Growth Factor beta
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Vimentin
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Interleukin-4