Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice.
Allergic inflammation is mediated by Th2 cell-derived cytokines, including IL-4, IL-5, and IL-13, and down-regulated by IFN-gamma and IL-12. Tyk2 is a member of the Janus family of protein tyrosine kinases and is activated by a variety of cytokines: IFN-alphabeta, 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.
Seto
Yohei
Y
Department of Internal Medicine II, Chiba University School of Medicine, Japan.
Nakajima
Hiroshi
H
Suto
Akira
A
Shimoda
Kazuya
K
Saito
Yasushi
Y
Nakayama
Keiichi I
KI
Iwamoto
Itsuo
I
D000280:Administration, Inhalation; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D003433:Crosses, Genetic; D004804:Eosinophils / Q000276:immunology / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D020397:Goblet Cells / Q000473:pathology; D006965:Hyperplasia; D007073:Immunoglobulin E / Q000096:biosynthesis; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D053634:TYK2 Kinase; D018418:Th2 Cells / Q000201:enzymology* / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics* / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D011506:Proteins; D011948:Receptors, Antigen, T-Cell; D007073:Immunoglobulin E; D010047:Ovalbumin; D011505:Protein-Tyrosine Kinases; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse