CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production.
CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production.
复制标题
CD4 细胞分泌的、翻译后修饰的细胞因子 GIF 通过抑制 IL-4 产生的起始来抑制 Th2 反应。
DOI：
10.1073/pnas.0810035105
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发表时间：
2008
影响因子：
11.1
通讯作者：
Sugie,Katsuji
中科院分区：
文献类型：
--
作者：
Kim-Saijo,Misa;Janssen,EdithM;Sugie,Katsuji
辅助性T细胞2（Th 2）对IgE抗体和过敏性炎症的诱导至关重要，但在非过敏性个体中如何控制病理途径仍不清楚。在这里，我们报告，糖基化抑制因子（GIF）抑制Th 2效应产生。GIF是由编码巨噬细胞移动抑制因子（MIF）的相同基因编码的细胞因子。GIF缺陷小鼠表现出增强的T依赖性抗体形成，特别是IgE同种型和过敏性气道炎症，调节性T细胞的产生不受影响。GIF缺陷型巨噬细胞和树突状细胞显示对Toll样受体（TLR）配体的正常反应。GIF经历独特的翻译后修饰，半胱氨酸化。修饰的GIF主要由来自CD 4 + CD 25 −细胞的活化T细胞分泌，抑制相同细胞的IL-4产生，而未修饰的GIF则没有效果。骨髓嵌合体实验表明，T细胞源性GIF抑制分泌IL-4的Th效应子的产生。在CD 3/CD 28体外刺激的前24 h内，初始CD 4细胞分泌的GIF作用于相同的细胞，维持活化T细胞核因子（NFAT）c2在细胞核内的表达，并抑制IL-4 mRNA的表达。因此，GIF代表了幼稚CD 4细胞产生Th 2细胞的自我调节机制，其中翻译后修饰起着至关重要的作用。
T helper 2 (Th2) cells are critical to the induction of IgE antibody and allergic inflammation, but how the pathological pathways are controlled in nonallergic individuals remains unclear. Here we report that glycosylation-inhibiting factor (GIF) suppresses Th2 effector generation. GIF is a cytokine encoded by the same gene that codes for macrophage migration inhibitory factor (MIF). GIF-deficient mice demonstrated enhanced T-dependent antibody formation especially of IgE isotype and allergic airway inflammation with the generation of regulatory T cells unaffected. GIF-deficient macrophages and dendritic cells revealed normal responsiveness to toll-like receptor (TLR) ligands. GIF undergoes a unique posttranslational modification, cysteinylation. The modified GIF, mainly secreted by activated T cells derived from CD4+CD25−cells, inhibited IL-4 production by the same cells whereas the unmodified GIF showed no effect. Bone marrow chimera experiment demonstrated that T cell-derived GIF suppressed the generation of Th effectors that secrete IL-4. During the first 24 h of CD3/CD28 stimulationin vitro, GIF secreted from naïve CD4 cells acted on the same cells, maintained nuclear factor of activated T cells (NFAT)c2 in the nucleus, and repressed IL-4 mRNA levels. Thus, GIF represents a self-regulatory mechanism of Th2 cell generation from naïve CD4 cells, in which the posttranslational modification plays a crucial role.