IL-4 in Autoimmune Flaky Skin Mice

Flaky skin mutant (Ttc7fsn) mice display systemic immune dysfunction including splenomegaly, glomerulonephritis, elevated levels of serum IgE, a substantial increase in the number of splenic B cells and a dramatic increase in IL-4 production. Previous work indicated constitutively activated Stat6 in splenic B cells; herein we have demonstrated this to be the result of continuous IL-4 signaling as nuclear localization studies suggested B cells have the ability to turn over activated Stat6 ex vivo when the IL-4 signal is removed. In addition, actinomycin D studies provide evidence for an increase in IL-4 mRNA stability which leads to dramatically increased IL-4 protein production resulting in a driving force toward systemic autoimmunity. Although the function of the Ttc7fsn gene is as yet unknown, we suggest that it may lead to a greater understanding of the mechanisms involved in IL-4 regulation.鳞屑样皮肤突变（Ttc7fsn）小鼠表现出系统性免疫功能异常，具体涵盖脾脏肿大、肾小球肾炎、血清免疫球蛋白E（IgE）水平升高、脾脏B细胞数量显著增多，以及白细胞介素4（IL-4）生成量大幅升高。既往研究发现，该小鼠的脾脏B细胞中存在信号转导与转录激活因子6（Stat6）的持续性激活；本研究证实，该激活现象源于持续的IL-4信号通路激活。核定位实验结果显示，当移除IL-4信号后，B细胞可在体外（ex vivo）对活化状态的Stat6进行周转。此外，放线菌素D实验证实，IL-4 mRNA的稳定性显著提升，进而使IL-4蛋白生成量大幅升高，最终成为系统性自身免疫病的潜在驱动因素。尽管目前Ttc7fsn基因的功能尚未明确，但本研究提示，该突变模型或可为阐明IL-4调控的相关分子机制提供新的视角。