Abstract
In a murine model of allergic asthma, we found that Tyk-2((-/-)) asthmatic mice have induced peribronchial collagen deposition, mucosal type mast cells in the lung, IRF4 and hyperproliferative lung Th2 CD4(+) effector T cells over-expressing IL-3, IL-4, IL-5, IL-10 and IL-13. We also observed increased Th9 cells expressing IL-9 and IL-10 as well as T helper cells expressing IL-6, IL-10 and IL-21 with a defect in IL-17A and IL-17F production. This T helper phenotype was accompanied by increased SOCS3 in the lung of Tyk-2 deficient asthmatic mice. Finally, in vivo treatment with rIL-17A inhibited local CD4(+)CD25(+)Foxp3(+) T regulatory cells as well as Th2 cytokines without affecting IL-9 in the lung. These results suggest a role of Tyk-2 in different subsets of T helper cells mediated by SOCS3 regulation that is relevant for the treatment of asthma, cancer and autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Asthma / immunology
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Asthma / metabolism
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Asthma / pathology*
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / immunology
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Cell Differentiation
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Cell Proliferation
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Cytokines / metabolism
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Disease Models, Animal
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Interleukin-17 / genetics
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Interleukin-17 / metabolism
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Interleukin-17 / pharmacology
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Lung / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Ovalbumin / immunology
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Phenotype
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / genetics
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Recombinant Proteins / pharmacology
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins / metabolism
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T-Lymphocytes, Helper-Inducer / drug effects
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T-Lymphocytes, Helper-Inducer / immunology
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T-Lymphocytes, Helper-Inducer / metabolism*
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TYK2 Kinase / genetics
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TYK2 Kinase / metabolism*
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Th17 Cells / cytology
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Th17 Cells / immunology
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Th17 Cells / metabolism*
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Th2 Cells / cytology
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Th2 Cells / immunology
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Th2 Cells / metabolism
Substances
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Cytokines
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Interleukin-17
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Recombinant Proteins
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Socs3 protein, mouse
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Suppressor of Cytokine Signaling 3 Protein
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Suppressor of Cytokine Signaling Proteins
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Ovalbumin
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TYK2 Kinase
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Tyk2 protein, mouse