Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells
Divergent effects of IL-12 and IL-23 on the production of IL-17 by human T cells
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DOI：
10.1002/eji.200535239
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发表时间：
2006-03-01
影响因子：
5.4
通讯作者：
Verreck, FAW
中科院分区：
文献类型：
--
作者：
Hoeve, MA;Savage, NDL;Verreck, FAW
IL-23被认为是自身免疫性疾病中的主要促炎介质，直到最近才将其作用归因于其相关细胞因子IL-12。IL-23是一种IL-12 p40/p19异二聚体蛋白，与IL-12 R β 1/IL-23 R受体复合物结合。缺乏p19、p40或IL-12 R β 1的小鼠对实验性自身免疫性脑脊髓炎或胶原诱导的关节炎具有抗性。然而，奇怪的是，IL-12 R β 2-和IL-12 p35-缺陷小鼠显示出疾病易感性的显著增加，表明IL-23和IL-12在调节炎症过程中的不同作用。IL-23诱导IL-17，其介导炎症和组织重塑，但IL-12在这方面的作用仍未确定。我们研究了外源性（重组）和内源性（巨噬细胞衍生的）IL-12和IL-23对人T细胞中IL-17诱导的作用。IL-23增强IL-17分泌，IL-2、IL-15、IL-18和IL-21也是如此。相反，IL-12介导IL-17产生的特异性抑制。这些数据支持IL-23通过刺激T淋巴细胞产生IL-17在炎症中的作用，并且重要地表明通过特异性抑制IL-17分泌对IL-12的新的调节功能。因此，这些数据扩展了先前的报道，这些报道表明IL-23和IL-12由于不同的受体表达和信号转导复合物而具有独特的功能，并为免疫，炎症和免疫病理学的调节提供了新的见解。
IL-23 is regarded as a major pro-inflammatory mediator in autoimmune disease, a role which until recently was ascribed to its related cytokine IL-12. IL-23, an IL-12p40/p19 heterodimeric protein, binds to IL-12R beta 1/IL-23R receptor complexes. Mice deficient for p19, p40 or IL-12R beta 1 are resistant to experimental autoimmune encephalomyelitis or collagen-induced arthritis. Paradoxically, however, IL-12R beta 2- and IL-12p35-deficient mice show remarkable increases in disease susceptibility, suggesting divergent roles of IL-23 and IL-12 in modulating inflammatory processes. IL-23 induces IL-17, which mediates inflammation and tissue remodeling, but the role of IL-12 in this respect remains unidentified. We investigated the roles of exogenous (recombinant) and endogenous (macrophage-derived) IL-12 and IL-23, on IL-17-induction in human T-cells. IL-23 enhanced IL-17 secretion, as did IL-2, IL-15, IL-18 and IL-21. In contrast, IL-12 mediated specific inhibition of IL-17 production. These data support the role of IL-23 in inflammation through stimulating IL-17 production by T lymphocytes, and importantly indicate a novel regulatory function for IL-12 by specifically suppressing IL-17 secretion. These data therefore extend previous reports that had indicated unique functions for IL-23 and IL-12 due to distinct receptor expression and signal transduction complexes, and provide novel insights into the regulation of immunity, inflammation and immunopathology.