Suppressor. of cytokine signaling 1 inhibits IL-10-mediated immune responses
Suppressor. of cytokine signaling 1 inhibits IL-10-mediated immune responses
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DOI：
10.4049/jimmunol.170.3.1383
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发表时间：
2003-02-01
影响因子：
4.4
通讯作者：
Bromberg, JS
中科院分区：
文献类型：
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作者：
Ding, YZ;Chen, DM;Bromberg, JS
IL-10已被证明是通过控制各种其他细胞因子的产生和功能来调节炎症反应的关键细胞因子。细胞因子信号转导抑制因子(SOCS)基因产物是一类细胞质分子，是负调控细胞因子信号转导的重要介体。已有研究表明，IL-10诱导SOCS3的表达，而SOCS3的强制结构性表达抑制了IL-10/STAT3的激活和内毒素诱导的巨噬细胞的激活。在这篇报道中，我们发现，除了SOCS3的表达外，IL-10还能诱导所有受试细胞系的SOCS1表达上调，包括BA/F3Pro-B细胞、MC/9肥大细胞、M1白血病细胞、U3A人成纤维细胞和原代小鼠的CD4(+)T细胞。SOCS分子的诱导依赖于IL-10R1对STAT3的激活。过表达SOCS蛋白的细胞系表明，SOCS1和SOCS3而不是SOCS2能够部分抑制IL-10介导的STAT3激活和增殖反应。用干扰素-γ处理M1细胞可诱导SOCS1的表达，并降低IL-10介导的STAT3活性和细胞生长抑制。IL-10诱导的SOCS与多种细胞类型中的干扰素-γ信号的抑制有关，而且这种抑制不依赖于EL-10R的C末端丝氨酸残基，而这是其他抗炎反应所必需的。因此，目前的结果表明SOCK和SOCS3都是由IL-10诱导的，并且可能是IL-10和干扰素-γ信号的重要抑制物。IL-10诱导的SOCS1可能直接抑制IL-10干扰素-γ信号，而抑制其他促炎细胞因子反应可能通过IL-10R1介导的额外机制。
IL-10 has proved to be a key cytokine in regulating inflammatory responses by controlling the production and function of various other cytokines. The suppressor of cytokine signaling (SOCS) gene products are a family of cytoplasmic molecules that are essential mediators for negatively regulating cytokine signaling. It has been previously shown that IL-10 induced SOCS3 expression and that forced constitutive expression of SOCS3 inhibits IL-10/STAT3 activation and LPS-induced macrophage activation. In this report, we show that, in addition to SOCS3 expression, IL-10 induces SOCS1 up-regulation in all cell lines tested, including Ba/F3 pro-B cells, MC/9 mast cells, M1 leukemia cells, U3A human fibroblasts, and primary mouse, CD4(+) T cells. Induction of SOCS molecules is dependent on STAT3 activation by IL-10R1. Cell lines constitutively overexpressing SOCS proteins demonstrated that SOCS1 and SOCS3, but not SOCS2, are able to partially inhibit IL-10-mediated STAT3 activation and proliferative responses. Pretreatment of M1 cells with IFN-gamma resulted in SOCS1 induction and a reduction of IL-10-mediated STAT3 activation and cell growth inhibition. IL-10-induced SOCS is associated with the inhibition of IFN-gamma signaling in various cell types, and this inhibition is independent of C-terminal serine residues of the EL-10R, previously shown to be required for other anti-inflammatory responses. Thus, the present results show that both SOCK and SOCS3 are induced by IL-10 and may be important inhibitors of both IL-10 and IFN-gamma signaling. IL-10-induced SOCS1 may directly inhibit IL-10 IFN-gamma signaling, while inhibition of other proinflammatory cytokine responses may use additional IL-10R1-mediated mechanisms.