Interleukin-10 Inhibits Expression of Both Interferon – and Interferon γ– Induced Genes by Suppressing Tyrosine Phosphorylation of STAT1
Interleukin-10 Inhibits Expression of Both Interferon – and Interferon γ– Induced Genes by Suppressing Tyrosine Phosphorylation of STAT1
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DOI：
10.1182/blood.v93.5.1456.404a34_1456_1463
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发表时间：
1999-03
期刊：
影响因子：
20.3
通讯作者：
S. Ito;P. Ansari;M. Sakatsume;H. Dickensheets;N. Vázquez;R. Donnelly;A. Larner;D. Finbloom
中科院分区：
文献类型：
--
作者：
S. Ito;P. Ansari;M. Sakatsume;H. Dickensheets;N. Vázquez;R. Donnelly;A. Larner;D. Finbloom
白细胞介素-10（IL-10）有助于维持辅助性T淋巴细胞2（Th 2）表型中的极化辅助性T细胞。该过程的一部分涉及预防Th 1细胞的发育，Th 1细胞是干扰素γ（IFNγ）的主要来源，是单核细胞的有效激活剂和Th 2增殖的抑制剂。由于单核细胞和巨噬细胞是Th 1型反应（如迟发型超敏反应）的重要介质，因此我们试图确定IL-10是否可以直接介导这些细胞中IFNγ和IFN γ诱导的基因表达抑制。将高度纯化的单核细胞与IL-10孵育60至90分钟，然后加入IFNγ或IFN γ。IL-10预孵育导致几个IFN诱导的基因，如IP-10，ISG 54和细胞间粘附分子-1的基因表达的抑制。基因表达的降低是由于IL-10能够抑制IFN诱导的信号转导和转录激活因子（STAT）因子组装到IFN β和IFNγ诱导基因的特异性启动子基序上。这是通过阻止IFN诱导的STAT 1酪氨酸磷酸化来实现的，STAT 1是IFN β和IFNγ诱导的DNA结合复合物的组分。因此，IL-10可以通过抑制STAT 1的酪氨酸磷酸化直接抑制IFN γ和IFNγ诱导的单核细胞中STAT依赖性早期反应基因的表达。这可能是通过IL-10诱导细胞因子信号转导抑制因子3（SOCS 3）基因表达的能力而发生的。
Interleukin-10 (IL-10) helps maintain polarized T-helper cells in a T-helper lymphocyte 2 (Th2) phenotype. Part of this process involves the prevention of the development of Th1 cells, which are a primary source of interferon γ (IFNγ), a potent activator of monocytes and an inhibitor of Th2 proliferation. Because monocytes and macrophages are important mediators of Th1-type responses, such as delayed-type hypersensitivity, we sought to determine if IL-10 could directly mediate inhibition of IFNγ- and IFN-induced gene expression in these cells. Highly purified monocytes were incubated with IL-10 for 60 to 90 minutes before the addition of IFNγ or IFN. IL-10 preincubation resulted in the inhibition of gene expression for several IFN-induced genes, such as IP-10, ISG54, and intercellular adhesion molecule-1. The reduction in gene expression resulted from the ability of IL-10 to suppress IFN-induced assembly of signal transducer and activator of transcription (STAT) factors to specific promoter motifs on IFN- and IFNγ-inducible genes. This was accomplished by preventing the IFN-induced tyrosine phosphorylation of STAT1, a component of both IFN- and IFNγ-induced DNA binding complexes. Therefore, IL-10 can directly inhibit STAT-dependent early response gene expression induced by both IFN and IFNγ in monocytes by suppressing the tyrosine phosphorylation of STAT1. This may occur through the ability of IL-10 to induce expression of the gene, suppressor of cytokine signaling 3 (SOCS3).