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* Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan; and
Medicine and Biosystemic Science, Graduate School of Medical Sciences, and
Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
Allergic inflammation is mediated by Th2 cell-derived cytokines,
including IL-4, IL-5, and IL-13, and down-regulated by IFN-
and
IL-12. Tyk2 is a member of the Janus family of protein tyrosine kinases
and is activated by a variety of cytokines: IFN-
, IL-6, IL-10,
IL-12, and IL-13. In this study, we investigated the role of Tyk2 in
the regulation of Ag-induced Th cell differentiation and Ag-induced
allergic inflammation in the airways using Tyk2-deficient
(Tyk2-/-) mice. When splenocytes were stimulated with
antigenic peptide, IL-12-mediated Th1 cell differentiation was
decreased, but IL-4-mediated Th2 cell differentiation was increased in
Tyk2-/- mice. In vivo, Ag-specific IgE and IgG1
production was increased, but Ag-specific IgG2a production was
decreased in Tyk2-/- mice as compared with those in
control mice. In addition, Ag-induced eosinophil and CD4+ T
cell recruitment, as well as the production of Th2 cytokines in the
airways, was increased in Tyk2-/- mice. Adoptive transfer
experiments revealed that CD4+ T cells were responsible for
the enhanced Ag-induced eosinophil recruitment in Tyk2-/-
mice. In contrast, although the level of IL-13 was increased in the
airways of Tyk2-/- mice after Ag inhalation, the number
of goblet cells, as well as Muc5ac mRNA
expression, was decreased in Tyk2-/- mice. Together,
these results indicate that Tyk2 plays a bilateral role in the
regulation of allergic inflammation in the airways: Tyk2 plays a role
in the down-regulation of Th2 cell-mediated Ab production and
eosinophil recruitment in the airways by regulating Th1/Th2 balance
toward Th1-type, while Tyk2 is necessary for the induction of
IL-13-mediated goblet cell hyperplasia in the
airways.
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