Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
J Immunol. 2011 Jun 15;186(12):6762-70. doi: 10.4049/jimmunol.1003638. Epub 2011 May 6.
Murine Aim2 and Ifi202 genes (encoding for the Aim2 and p202 proteins) are members of the IFN-inducible Ifi200 gene family. The Aim2 deficiency in mice activates IFN signaling and stimulates the expression of the lupus susceptibility gene, the Ifi202, located within the NZB autoimmunity 2 (Nba2) interval. Given that the deficiency in the expression of the Fcgr2b gene (encoding for the inhibitory FcγRIIB receptor) is associated with increased lupus susceptibility in mice, we investigated whether the Aim2 protein could regulate the expression of Fcgr2b gene. In this article, we report that Aim2 deficiency in mice suppresses the expression of the FcγRIIB receptor. Interestingly, the Fcgr2b-deficient cells expressed increased levels of the IFN-β, activated IFN signaling, and expressed reduced levels of the Aim2 protein. Treatment of splenic cells with IFN-α or -γ reduced levels of the FcγRIIB mRNA and protein and also decreased the activity of the FcγRIIB p(-729/+585) Luc reporter. Moreover, levels of the FcγRIIB receptor were significantly higher in the Stat1-deficient splenic cells than in the wild-type cells. Accordingly, increased expression of IFN-β in lupus-prone B6.Nba2-ABC mice, as compared with non-lupus-prone C57BL/6 (B6) or B6.Nba2-C mice, was associated with reduced expression of the FcγRIIB receptor. Notably, overexpression of the p202 protein in cells decreased the expression of the Aim2 gene, activated the IFN response, and suppressed the expression of the Fcgr2b gene. These observations demonstrate that the expression of Aim2 protein is required to maintain the expression of the Fcgr2b gene and also predict epistatic interactions between the Ifi200 genes and the Fcgr2b gene within the Nba2 interval.
鼠的 Aim2 和 Ifi202 基因（编码 Aim2 和 p202 蛋白）是 IFN 诱导的 Ifi200 基因家族的成员。在小鼠中，Aim2 的缺失会激活 IFN 信号通路，并刺激位于 NZB 自身免疫 2（Nba2）区间内的狼疮易感性基因 Ifi202 的表达。鉴于 Fcgr2b 基因（编码抑制性 FcγRIIB 受体）表达的缺失与小鼠狼疮易感性增加有关，我们研究了 Aim2 蛋白是否可以调节 Fcgr2b 基因的表达。在本文中，我们报告小鼠的 Aim2 缺失会抑制 FcγRIIB 受体的表达。有趣的是，Fcgr2b 缺陷细胞表达了更高水平的 IFN-β，激活了 IFN 信号通路，并表达了更低水平的 Aim2 蛋白。用 IFN-α 或 -γ 处理脾细胞可降低 FcγRIIB mRNA 和蛋白的水平，并降低 FcγRIIB p(-729/+585)Luc 报告基因的活性。此外，Stat1 缺陷的脾细胞中的 FcγRIIB 受体水平明显高于野生型细胞。因此，与非狼疮易感的 C57BL/6（B6）或 B6.Nba2-C 小鼠相比，狼疮易感的 B6.Nba2-ABC 小鼠中 IFN-β 的表达增加与 FcγRIIB 受体的表达降低有关。值得注意的是，细胞中 p202 蛋白的过表达降低了 Aim2 基因的表达，激活了 IFN 反应，并抑制了 Fcgr2b 基因的表达。这些观察结果表明，Aim2 蛋白的表达是维持 Fcgr2b 基因表达所必需的，并且预测了 Nba2 区间内 Ifi200 基因和 Fcgr2b 基因之间的上位性相互作用。
