Hou Wanqiu, Wu Yadi, Sun Shuhui, Shi Mude, Sun Yue, Yang Cuihong, Pei Gang, Gu Yundi, Zhong Cuiping, Sun Bing
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
J Immunol. 2003 Feb 15;170(4):1728-36. doi: 10.4049/jimmunol.170.4.1728.
Pertussis toxin (PTX) has been widely used as an adjuvant to induce Th1-mediated organ-specific autoimmune diseases in animal models. However, the cellular and molecular mechanisms remain to be defined. In this study, we showed that dendritic cells (DC) stimulated with PTX (PTX-DC) were able to substitute for PTX to promote experimental autoimmune uveitis (EAU). EAU induced by PTX-DC revealed a typical Th1 response, characterized by high uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP)-specific IFN-gamma and IL-12 production in the draining lymph nodes, as well as increased levels of anti-IRBP IgG2a and decreased levels of anti-IRBP IgG1 in the serum of IRBP-immunized mice. Furthermore, PTX-DC preferentially induced T cells to produce the Th1 cytokine, IFN-gamma. After being stimulated with PTX, DC exhibited up-regulation of MHC class II, CD80, CD86, CD40, and DEC205. PTX-DC had also increased allostimulatory capacity and IL-12 and TNF-alpha production. Serum IL-12 was increased in naive mice that received PTX-DC i.p. In addition, PTX activated extracellular signal-regulated kinase in DC. Following the inhibition of extracellular signal-regulated kinase signaling, the maturation of PTX-DC was reduced. Subsequently, the ability of PTX-DC to promote IFN-gamma production by T cells in vitro and to induce EAU in vivo was blocked. The results suggest that PTX might exert an adjuvant effect on DC to promote their maturation and the production of proinflammatory cytokines, thereby eliciting a Th1 response.
百日咳毒素（PTX）已被广泛用作佐剂，以在动物模型中诱导Th1介导的器官特异性自身免疫性疾病。然而，其细胞和分子机制仍有待确定。在本研究中，我们发现用PTX刺激的树突状细胞（DC）（PTX-DC）能够替代PTX来促进实验性自身免疫性葡萄膜炎（EAU）。PTX-DC诱导的EAU表现出典型的Th1反应，其特征在于引流淋巴结中高致葡萄膜炎性视网膜抗原光感受器间类视黄醇结合蛋白（IRBP）特异性IFN-γ和IL-12的产生，以及IRBP免疫小鼠血清中抗IRBP IgG2a水平升高和抗IRBP IgG1水平降低。此外，PTX-DC优先诱导T细胞产生Th1细胞因子IFN-γ。在用PTX刺激后，DC表现出MHC II类、CD80、CD86、CD40和DEC205的上调。PTX-DC还增强了同种异体刺激能力以及IL-12和TNF-α的产生。接受腹腔注射PTX-DC的未免疫小鼠血清IL-12增加。此外，PTX激活DC中的细胞外信号调节激酶。在抑制细胞外信号调节激酶信号传导后，PTX-DC的成熟受到抑制。随后，PTX-DC在体外促进T细胞产生IFN-γ以及在体内诱导EAU的能力被阻断。结果表明，PTX可能对DC发挥佐剂作用，促进其成熟和促炎细胞因子的产生，从而引发Th1反应。
