IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells
IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells
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DOI：
10.1002/eji.200737810
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发表时间：
2007-11-01
影响因子：
5.4
通讯作者：
Liew, Foo Y.
中科院分区：
文献类型：
--
作者：
Niedbala, Wanda;Wei, Xiao-qing;Liew, Foo Y.
EB病毒诱导基因3(EBI3)和IL-12的p35亚基在人和小鼠体内形成异源二聚体。我们构建了一种异二聚体蛋白，将EBI3和p35共价连接起来，形成了一种新的细胞因子，我们现在称之为IL-35。IL-35的Fc融合蛋白在体外用固定化的抗CD3和抗CD28抗体刺激小鼠CD4(+)CD25(+)和CD4(+)CD25(-)T细胞增殖。IL-35扩增的CD4(+)CD25(+)T细胞群表达Foxp3并产生高水平的IL-10，而IL-35诱导的CD4(+)CD25(-)T细胞产生干扰素-γ，但不产生IL-4。体外扩增的CD4(+)CD25(+)T细胞保留了对CD4(+)CD25(-)效应细胞的抑制功能。此外，当IL-35与可溶性抗CD3抗体和抗原提呈细胞共同培养时，可抑制CD4(+)CD25(-)效应细胞的增殖。此外，IL-35在体外对Th17细胞的分化有抑制作用。在体内，IL-35有效地减轻了已建立的胶原蛋白诱导的小鼠关节炎，同时抑制了IL-17的产生，但促进了干扰素-γ的合成。因此，IL-35是一种新型的抗炎细胞因子，通过扩增调节性T细胞和抑制Th17细胞发育来抑制免疫反应。
Epstein-Barr virus-induced gene 3 (EBI3) and the p35 subunit of IL-12 have been reported to form a heterodimeric hematopoietin in human and mouse. We have constructed a heterodimeric protein covalently linking EBI3 and p35, to form a novel cytokine which we now call IL-35. The Fc fusion protein of IL-35 induced proliferation of murine CD4(+)CD25(+) and CD4(+)CD25(-) T cells when stimulated with immobilized anti-CD3 and anti-CD28 antibodies in vitro. The IL-35-expanded CD4(+)CD25(+) T cell population expressed Foxp3 and produced elevated levels of IL-10, whereas the IL-35-induced CD4(+)CD25(-) T cells produced IFN-gamma but not IL-4. The in vitro expanded CD4(+)CD25(+) T cells retained their suppressive functions against CD4(+)CD25(-) effector cells. Furthermore, when cultured with soluble anti-CD3 antibody and antigen-presenting cells, IL-35 suppressed the proliferation of CD4(+)CD25(-) effector cells. Moreover, IL-35 inhibited the differentiation of Th17 cells in vitro. In vivo, IL-35 effectively attenuated established collagen-induced arthritis in mice, with concomitant suppression of IL-17 production but enhanced IFN-gamma synthesis. Thus, IL-35 is a novel anti-inflammatory cytokine suppressing the immune response through the expansion of regulatory T cells and suppression of Th17 cell development.