Stat1 combines signals derived from IFN-γ and LPS receptors during macrophage activation
Stat1 combines signals derived from IFN-γ and LPS receptors during macrophage activation
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DOI：
10.1093/emboj/17.13.3660
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发表时间：
1998-07-01
期刊：
影响因子：
11.4
通讯作者：
Decker, T
中科院分区：
文献类型：
--
作者：
Kovarik, P;Stoiber, D;Decker, T
免疫反应过程中巨噬细胞的完全激活是由激活细胞因子干扰素-γ (IFN-γ) 和第二种刺激（通常是微生物产物）的刺激引起的。巨噬细胞的细菌感染或细菌脂多糖 (LPS) 处理会导致 Ser727 (S727) 上的 Stat1 快速磷酸化，而与伴随的酪氨酸磷酸化无关。 IFN-γ 也导致 S727 快速磷酸化。在这两种情况下，用丝氨酸激酶抑制剂 H7 预处理细胞都会降低 S727 磷酸化。当巨噬细胞依次或同时用 LPS 和 IFN-γ 处理时，Tyr701 (Y701) 和 S727 上磷酸化的分子库显着增加。一致地，如果细胞用细菌 LPS 预处理，则响应 IFN-γ 的 Stat1 依赖性转录显着增强。非酪氨酸磷酸化级分中 S727 磷酸化 Stat1 的相对量明显小于酪氨酸磷酸化级分中的相对量。没有发现证据表明 S727 磷酸化对 IFN-γ 引起的 Y701 磷酸化有影响。因此，Stat1 的丝氨酸和酪氨酸磷酸化是彼此独立引起的，但丝氨酸激酶可能在 IFN-γ 应答过程中优先识别酪氨酸磷酸化的 Stat1。数据表明 Stat1 是巨噬细胞促炎症反应中免疫刺激的汇聚点。
Complete activation of macrophages during immune responses results from stimulation with the activating cytokine interferon-gamma (IFN-gamma) and a second stimulus, usually a microbial product. Bacterial infection of macrophages, or treatment with bacterial lipopolysaccharide (LPS), resulted in rapid Stat1 phosphorylation on Ser727 (S727) independently of concomitant tyrosine phosphorylation. IFN-gamma also caused rapid phosphorylation of S727. In both situations, S727 phosphorylation was reduced by pre-treatment of cells with the serine kinase inhibitor H7. When macrophages were treated sequentially or simultaneously with LPS and IFN-gamma, the pool of molecules phosphorylated on both Tyr701 (Y701) and S727 was strongly increased. Consistently, Stat1-dependent transcription in response to IFN-gamma was significantly enhanced if the cells were pre-treated with bacterial LPS. The relative amount of S727-phosphorylated Stat1 in the non-tyrosine phosphorylated fraction was considerably smaller than that in the tyrosine-phosphorylated fraction. No evidence was found for an effect of S727 phosphorylation on the phosphorylation of Y701 by IFN-gamma. Thus, serine and tyrosine phosphorylation of Stat1 are caused independently of each other, but the serine kinase may recognize tyrosine-phosphorylated Stat1 preferentially in the course of an IFN-gamma response. The data suggest Stat1 to be a convergence point for immunological stimuli in a macrophage proinflammatory response.