Ito S, Ansari P, Sakatsume M, Dickensheets H, Vazquez N, Donnelly R P, Larner A C, Finbloom D S
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD, USA.
Blood. 1999 Mar 1;93(5):1456-63.
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 gamma (IFNgamma), 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 IFNgamma- and IFNalpha-induced gene expression in these cells. Highly purified monocytes were incubated with IL-10 for 60 to 90 minutes before the addition of IFNgamma or IFNalpha. 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 IFNalpha- and IFNgamma-inducible genes. This was accomplished by preventing the IFN-induced tyrosine phosphorylation of STAT1, a component of both IFNalpha- and IFNgamma-induced DNA binding complexes. Therefore, IL-10 can directly inhibit STAT-dependent early response gene expression induced by both IFNalpha and IFNgamma 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).
白细胞介素-10（IL-10）有助于维持极化的T辅助细胞处于T辅助淋巴细胞2（Th2）表型。这一过程的部分机制涉及阻止Th1细胞的发育，Th1细胞是γ干扰素（IFNγ）的主要来源，γ干扰素是单核细胞的强效激活剂和Th2增殖的抑制剂。由于单核细胞和巨噬细胞是Th1型反应（如迟发型超敏反应）的重要介质，我们试图确定IL-10是否能直接介导对这些细胞中IFNγ和IFNα诱导的基因表达的抑制作用。在添加IFNγ或IFNα之前，将高度纯化的单核细胞与IL-10孵育60至90分钟。IL-10预孵育导致几种IFN诱导基因的表达受到抑制，如IP-10、ISG54和细胞间黏附分子-1。基因表达的降低是由于IL-10能够抑制IFN诱导的信号转导子和转录激活子（STAT）因子与IFNα和IFNγ诱导基因上特定启动子基序的组装。这是通过阻止IFN诱导的STAT1酪氨酸磷酸化来实现的，STAT1是IFNα和IFNγ诱导的DNA结合复合物的组成部分。因此，IL-10可通过抑制STAT1的酪氨酸磷酸化，直接抑制单核细胞中IFNα和IFNγ诱导的STAT依赖性早期反应基因表达。这可能是通过IL-10诱导细胞因子信号转导抑制因子3（SOCS3）基因表达的能力来实现的。
