IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways
IL-10 inhibits macrophage activation and proliferation by distinct signaling mechanisms: evidence for Stat3-dependent and -independent pathways
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DOI：
10.1093/emboj/17.4.1006
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发表时间：
1998-02-16
期刊：
影响因子：
11.4
通讯作者：
Mui, ALF
中科院分区：
文献类型：
--
作者：
O'Farrell, AM;Liu, Y;Mui, ALF
白细胞介素-10 （IL-10）通过抑制巨噬细胞的激活来限制炎症反应，在巨噬细胞中，IL-10激活Stat1和Stat3。我们分析了J774小鼠巨噬细胞系和表达野生型hIL-10R的J774细胞的IL-10反应，突变型hIL-10R缺乏两个参与Stat3募集的膜远端酪氨酸（hIL-10R- tyr (FF)），截断的Stat3 （Delta Stat3）作为显性阴性，或诱导活性的Stat3- gyraseb嵌合体（Stat3- gyrb）。产生一种中和性抗mIL-10R单克隆抗体，阻断内源性mIL-10R的功能，IL-10抑制J774细胞和正常骨髓源性巨噬细胞的增殖，但不抑制表达il - 10rtyr （FF）的J774细胞的增殖，古霉素使Stat3- gyrb二聚化模仿IL-10的作用，表达Delta Stat3阻断IL-10的抗增殖活性，对于巨噬细胞的去活化反应。hIL10R-Tyr（FF）不能介导脂多糖诱导的TNF α、IL-1 β或CD86表达的抑制，而Delta Stat3对这些IL-10反应没有明显的干扰，因此介导IL-10的抗增殖和巨噬细胞去活化反应的信号需要IL-10R的两个膜远端酪氨酸，但Stat3似乎仅在抗增殖反应中起作用。
Interleukin-10 (IL-10) limits inflammatory responses by inhibiting macrophage activation, In macrophages, IL-10 activates Stat1 and Stat3. We characterized IL-10 responses of the J774 mouse macrophage cell line, and of J774 cells expressing wild-type hIL-10R, mutant hIL-10R lacking two membrane-distal tyrosines involved in recruitment of Stat3 (hIL-10R-Tyr(FF)), a truncated Stat3 (Delta Stat3) which acts as a dominant negative, or an inducibly active Stat3-gyraseB chimera (Stat3-GyrB). A neutralizing anti-mIL-10R monoclonal antibody was generated to block the function of endogenous mIL-10R, IL-10 inhibited proliferation of J774 cells and of normal bone marrow-derived macrophages, but not J774 cells expressing hIL-10RTyr(FF), Dimerization of Stat3-GyrB by coumermycin mimicked the effect of IL-10, and expression of Delta Stat3 blocked the anti-proliferative activity of IL-10, For macrophage de-activation responses, hIL10R-Tyr(FF) could not mediate inhibition of lipopolysaccharide-induced TNF alpha, IL-1 beta or CD86 expression, while Delta Stat3 did not interfere detectably with these IL-10 responses, Thus signals mediating both anti-proliferative and macrophage de-activation responses to IL-10 require the two membrane-distal tyrosines of IL-10R, but Stat3 appears to function only in the anti-proliferative response.