Enhanced Th2 Cell-Mediated Allergic Inflammation in Tyk2-Deficient Mice

Abstract

Allergic inflammation is mediated by Th2 cell-derived cytokines, including IL-4, IL-5, and IL-13, and down-regulated by IFN-γ and IL-12. Tyk2 is a member of the Janus family of protein tyrosine kinases and is activated by a variety of cytokines: IFN-αβ, 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.

The H1 histamine receptor regulates allergic lung responses

“…Th2 cytokines are enhanced in allergic disease and are important regulators of allergic lung responses. Several studies have demonstrated enhanced allergic responses in animals with Th2-dominated phenotypes (34)(35)(36)(37). Thus, the reported Th2 bias of H1R -/-mice might have predicted an exaggerated allergic inflammatory response.…”

Involvement of Tyrosine Kinase-2 in Both the IL-12/Th1 and IL-23/Th17 Axes In Vivo

“…Gene-targeted Tyk2-deficient mice were backcrossed for at least eight generations onto BALB/c mice (8,25). Mice were kept under specific pathogen-free conditions and provided with food and water ad libitum.…”

Tyk2 Negatively Regulates Adaptive Th1 Immunity by Mediating IL-10 Signaling and Promoting IFN-γ-Dependent IL-10 Reactivation

“…Tyk2-deficient mice, unlike other Jak kinase mutants, are developmentally normal but have diminished signaling in response to IFN-␣␤ and IL-12 and exhibit partial susceptibility to certain viruses (3,4). Further characterization of the Tyk2 Ϫ/Ϫ mice revealed a critical role of Tyk2 in mediating not only LPS-induced endotoxin shock (5,6), but also allergic airway hypersensitivity (7). In addition, our laboratory has identified a naturally occurring mutation in the Tyk2 gene of the B10.Q/J strain of mice, which are spontaneously susceptible to Toxoplasma gondii and yet highly refractory to collagen-induced arthritis (8 -10).…”