Venuprasad K, Elly Chris, Gao Min, Salek-Ardakani Shahram, Harada Yohsuke, Luo Jun-Li, Yang Chun, Croft Michael, Inoue Kazushi, Karin Michael, Liu Yun-Cai
Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121, USA.
J Clin Invest. 2006 Apr;116(4):1117-26. doi: 10.1172/JCI26858. Epub 2006 Mar 23.
The immune system is capable of mounting robust responses against invading pathogens but refrains from attacking self. Many studies have focused on tolerance induction of Th1 cells, whose failure results in development of autoimmune diseases. However, the molecular mechanisms governing tolerance induction in Th2 cells and its relation to allergic responses remain unclear. Here we used both in vivo and in vitro protocols to demonstrate that Th2 cells either containing a mitogen and extracellular kinase kinase 1 (MEKK1) mutant or lacking JNK1 or the E3 ubiquitin ligase Itch cannot be tolerized. In a mouse allergic model, injection of high-dose tolerizing antigen failed to block the development of airway inflammation in Itch-/- mice. This study suggests that MEKK1-JNK signaling regulates Itch E3 ligase-mediated tolerogenic process in Th2 cells. These findings have therapeutic implications for allergic diseases.
免疫系统能够对入侵病原体发起强有力的反应，但不会攻击自身。许多研究聚焦于Th1细胞的耐受性诱导，Th1细胞诱导失败会导致自身免疫性疾病的发生。然而，调控Th2细胞耐受性诱导的分子机制及其与过敏反应的关系仍不清楚。在此，我们运用体内和体外实验方案证明，含有丝裂原和细胞外激酶激酶1（MEKK1）突变体的Th2细胞，或缺乏JNK1或E3泛素连接酶Itch的Th2细胞，均无法被诱导产生耐受性。在小鼠过敏模型中，注射高剂量的耐受性抗原未能阻止Itch基因敲除小鼠气道炎症的发展。本研究表明，MEKK1-JNK信号通路调节Itch E3连接酶介导的Th2细胞耐受性过程。这些发现对过敏性疾病具有治疗意义。
