Tenda Yoshiyuki, Yamashita Masakatsu, Kimura Motoko Y, Hasegawa Akihiro, Shimizu Chiori, Kitajima Masayuki, Onodera Atsushi, Suzuki Akane, Seki Nobuo, Nakayama Toshinori
Department of Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
J Allergy Clin Immunol. 2006 Sep;118(3):725-33. doi: 10.1016/j.jaci.2006.05.024. Epub 2006 Jul 28.
Nishiki-nezumi Cinnamon/Nagoya (NC/Nga) mice raised in nonair-controlled conventional circumstances spontaneously develop atopic dermatitis-like skin lesions; however, the underlying mechanisms remain unclear.
We wanted to identify the critical intracellular signaling molecules in T cells that induce atopic dermatitis-like skin legions in NC/Nga mice.
We examined the levels of signal transduction and cytokine production in T cells, particularly those in atopic dermatitis-like lesions induced by the topical injection of mite antigens in NC/Nga mice under specific pathogen-free conditions.
In NC/Nga mice maintained under specific pathogen-free conditions, the capability of T(H)1/T(H)2 and T cytotoxic 1/T cytotoxic 2 (Tc1/Tc2) cell differentiation increased significantly. T-cell antigen receptor-mediated activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase cascade and nuclear factor-kappaB (NF-kappaB) signaling were enhanced in NC/Nga T cells. The expression of T(H)2 cytokines (IL-4, IL-13, and IL-5) and that of GATA-binding protein 3 (GATA3), avian musculoaponeurotic fibrosarcoma (c-Maf), NF-kappaB, and activator protein 1 (AP1) selectively increased in draining lymph node T cells of NC/Nga mice. Moreover, the cell transfer of inhibitory NF-kappaB mutant-infected T(H)2 cells reduced ear thickness in the mite antigen-induced skin lesion of NC/Nga mice.
Hyperresponsive T(H)2 cells with an enhanced activity of NF-kappaB and AP1 play a crucial role in the pathogenesis of atopic dermatitis-like skin lesions in NC/Nga mice.
These results indicate potential therapeutic usefulness of developing selective inhibitors for NF-kappaB in the treatment of human atopic dermatitis.
在非空气控制的常规环境中饲养的西氏小鼠肉桂/名古屋（NC/Nga）小鼠会自发出现特应性皮炎样皮肤病变；然而，其潜在机制仍不清楚。
我们想要确定在NC/Nga小鼠中诱导特应性皮炎样皮肤病变的T细胞中的关键细胞内信号分子。
我们检测了T细胞中信号转导和细胞因子产生的水平，特别是在无特定病原体条件下，通过向NC/Nga小鼠局部注射螨抗原诱导的特应性皮炎样病变中的T细胞。
在无特定病原体条件下饲养的NC/Nga小鼠中，辅助性T细胞1/辅助性T细胞2（Th1/Th2）和细胞毒性T细胞1/细胞毒性T细胞2（Tc1/Tc2）细胞分化能力显著增强。NC/Nga T细胞中T细胞抗原受体介导的细胞外信号调节激酶/丝裂原活化蛋白激酶级联反应和核因子κB（NF-κB）信号传导增强。在NC/Nga小鼠引流淋巴结T细胞中，Th2细胞因子（白细胞介素-4、白细胞介素-13和白细胞介素-5）以及GATA结合蛋白3（GATA3）、禽肌动蛋白神经纤维肉瘤（c-Maf）、NF-κB和活化蛋白1（AP1）的表达选择性增加。此外，抑制性NF-κB突变体感染的Th2细胞的细胞转移减少了NC/Nga小鼠螨抗原诱导的皮肤病变中的耳厚度。
具有增强的NF-κB和AP1活性的高反应性Th2细胞在NC/Nga小鼠特应性皮炎样皮肤病变的发病机制中起关键作用。
这些结果表明开发NF-κB选择性抑制剂在治疗人类特应性皮炎方面具有潜在的治疗价值。
