Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice
Enhanced Th2 cell-mediated allergic inflammation in Tyk2-deficient mice
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DOI：
10.4049/jimmunol.170.2.1077
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发表时间：
2003-01-15
影响因子：
4.4
通讯作者：
Iwamoto, I
中科院分区：
文献类型：
--
作者：
Seto, Y;Nakajima, H;Iwamoto, I
变应性炎症是由Th2细胞来源的细胞因子介导的，包括IL-4、IL-5和IL-13，并被ifn - γ和IL-12下调。Tyk2是Janus蛋白酪氨酸激酶家族的一员，可被多种细胞因子激活：ifn - α、IL-6、IL-10、IL-12和IL-13。在这项研究中，我们利用Tyk2缺陷（Tyk2(-/-)）小鼠研究了Tyk2在ag诱导的Th细胞分化和ag诱导的气道变应性炎症中的调节作用。当抗原肽刺激脾细胞时，Tyk2（-/-）小鼠il -12介导的Th1细胞分化减少，而il -4介导的Th2细胞分化增加。在体内，与对照小鼠相比，Tyk2（-/-）小鼠的ag特异性IgE和IgG1产量增加，但ag特异性IgG2a产量减少。此外，在Tyk2（-/-）小鼠中，ag诱导的嗜酸性粒细胞和CD4+ T细胞募集以及气道中Th2细胞因子的产生均增加。过继性转移实验显示，CD4+ T细胞在Tyk2（-/-）小鼠中负责ag诱导的嗜酸性粒细胞募集增强。相比之下，虽然吸入Ag后Tyk2（-/-）小鼠气道中IL-13水平升高，但Tyk2（-/-）小鼠的杯状细胞数量和Muc5ac mRNA表达均下降。综上所述，这些结果表明Tyk2在气道变应性炎症的调节中发挥了双边作用：Tyk2通过调节Th1/Th2向Th1型的平衡，下调气道中Th2细胞介导的Ab产生和嗜酸性粒细胞募集，而Tyk2在气道中诱导il -13介导的杯状细胞增生是必需的。
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.