The production of IFN-γ by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4
The production of IFN-γ by IL-12/IL-18-activated macrophages requires STAT4 signaling and is inhibited by IL-4
复制标题
DOI：
10.4049/jimmunol.166.5.3075
复制
发表时间：
2001-03-01
影响因子：
4.4
通讯作者：
Bogdan, C
中科院分区：
文献类型：
--
作者：
Schindler, H;Lutz, MB;Bogdan, C
巨噬细胞在 IL-12 和 IL-18 联合刺激下释放 IFN-γ，但该过程的信号传导要求及其受其他细胞因子的调节尚不清楚。在这里，我们证明 STAT4 对于 IL-12/LL-18 诱导小鼠腹膜巨噬细胞产生 IFN-γ 是不可或缺的。我们之前发现 2 型 NO 合酶 (NOS2) 是 NK 细胞中 IL-12 诱导的 IFN-γ 产生的先决条件，但这些巨噬细胞不需要 IFN-γ 产生，单独的 IL-12 已经诱导 IFN-γ mRNA 的表达，但 STAT4 的核转位、IFN-γ 蛋白的释放以及随后的 NO 产生严格依赖于同时存在的 IL-18、NF-κB、它在 T 细胞中介导 IL-18 作用，仅被巨噬细胞中的 IL-12 和/或 IL-18 微弱激活。已知的巨噬细胞功能抑制剂（例如 IL-4 和 TGF-β）也抑制巨噬细胞 IFN-γ 的产生以及随后 NOS2 衍生的 NO 的产生。 IL-4 的抑制作用与 STAT6 的核转位平行，STAT6 在 EMSA 中能够与 STAT4 结合相同的 DNA 寡核苷酸。这些结果进一步定义了巨噬细胞产生 IFN-γ 的情况，并指出了各种细胞类型产生 IFN-γ 所需信号的多样性。
Macrophages release IFN-gamma on combined stimulation with IL-12 and IL-18, but the signaling requirements of this process and its regulation by other cytokines are unknown. Here, we demonstrate that STAT4 is indispensable for IL-12/LL-18-induced producHon of IFN-gamma by mouse peritoneal macrophages. Type 2 NO synthase (NOS2), which we previously found to be a prerequisite for IL-12-induced IFN- gamma production in NK cells, was not required for IFN-gamma production by these macrophages, IL-12 alone already induced the expression of IFN-gamma mRNA, but nuclear translocation of STAT4, the release of IFN-gamma protein, and the subsequent production of NO was strictly dependent on the simultaneous presence of IL-18, NF-kappaB, which mediates IL-18 effects in T cells, was only weakly activated by IL-12 and/or IL-18 in macrophages. Known inhibitors of macrophage functions (e.g,, IL-4 and TGF-beta) also suppressed macrophage IFN-gamma production and the subsequent production of NOS2-derived NO. The inhibitory effect of IL-4 was paralleled by nuclear translocation of STAT6, which in EMSAs was able to bind to the same DNA oligonucleotide as STAT4, These results further define the production of IFN-gamma by macrophages and point to a diversity in the signals required for IFN-gamma production by various cell types.