Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96
Essential roles of IL-12 and dendritic cells but not IL-23 and macrophages in lupus-like diseases initiated by cell surface HSP gp96
复制标题
DOI：
10.1002/eji.200636643
复制
发表时间：
2007-03-01
影响因子：
5.4
通讯作者：
Li, Zihai
中科院分区：
文献类型：
--
作者：
Dai, Jie;Liu, Bei;Li, Zihai
促炎细胞因子IL-23而非IL-12对器官特异性自身免疫性疾病的发病机制至关重要，包括实验性自身免疫性脑炎和胶原诱导的关节炎。IL-23在狼疮等系统性自身免疫性疾病中的作用尚不明确。我们在小鼠狼疮样疾病模型中解决了这个问题，该模型是由C57BL/6背景下ER热休克蛋白gp96的细胞表面强制表达引发的。我们发现，在这些小鼠的血清中，p40在疾病发作之前显著增加。然而，在表达用p35(-/-) BM重组的膜结合gp96的转基因小鼠中，自身免疫被消除，而用p19(-/-) BM重组的gp96则没有。此外，我们发现树突状细胞（DC）而不是巨噬细胞是p40的主要产生者。为了进一步剖析DC的作用，我们使用基于白喉毒素的诱导DC耗尽系统来耗尽DC。我们证明DC的完整性对自身免疫至关重要。因此，我们的研究结果表明，IL-12和DC对细胞表面gp96沉淀的狼疮样疾病的发病机制至关重要。本研究进一步强调了IL-12和IL-23之间的显著生物学差异。
Proinflammatory cytokine IL-23 but not IL-12 is critical for the pathogenesis of organ-specific autoimmune diseases including experimental autoimmune encephalitis and collagen-induced arthritis. The contribution by IL-23 in systemic autoimmune diseases such as lupus is undefined. We addressed this question in a murine lupus-like disease model, initiated by enforced cell-surface expression of an ER HSP gp96 in C57BL/6 background. We found a significant increase of p40 in the sera in these mice that preceded the onset of diseases. However, autoimmunity was abrogated in transgenic mice expressing membrane-bound gp96 reconstituted with p35(-/-) BM, but not with p19(-/-) BM. Moreover, we found that dendritic cells (DC) but not macrophages were the main producers of p40. To dissect the roles of DC further, we depleted DC using a diphtheria toxin-based inducible DC depletion system. We demonstrated that the integrity of DC was essential for autoimmunity. Our results thus revealed that IL-12 and DC are critical for the pathogenesis of lupus-like disease precipitated by cell surface gp96. This study further highlighted the significant biological differences between IL-12 and IL-23.