Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, PO Box 670056, Cincinnati, OH 45267, USA.
Int Immunol. 2013 Sep;25(9):521-9. doi: 10.1093/intimm/dxt015. Epub 2013 Jun 1.
The endoplasmic reticulum transmembrane protein, Unc93b1, is essential for trafficking of endosomal TLRs from the endoplasmic reticulum to endosomes. A genetic defect in the human UNC93B1 gene is associated with immunodeficiency. However, systemic lupus erythematosus (SLE) patients express increased levels of the UNC93B1 protein in B cells. Because SLE in patients and certain mouse models exhibits a sex bias and increased serum levels of type I interferons in patients are associated with the disease activity, we investigated whether the female sex hormone estrogen (E2) or type I interferon signaling could up-regulate the expression of the murine Unc93b1 gene. We found that steady-state levels of Unc93b1 mRNA and protein were measurably higher in immune cells (CD3(+), B220(+), CD11b(+) and CD11c(+)) isolated from C57BL/6 (B6) females than age-matched males. Moreover, treatment of CD11b(+) and B220(+) cells with E2 or interferons (IFN-α, IFN-β or IFN-γ) significantly increased the levels of Unc93b1 mRNA and protein. Accordingly, a deficiency of estrogen receptor-α or STAT1 expression in immune cells decreased the expression levels of the Unc93b1 protein. Interestingly, levels of Unc93b1 protein were appreciably higher in B6.Nba2 lupus-prone female mice compared with age-matched B6 females. Furthermore, increased expression of the interferon- and E2-inducible p202 protein in a murine macrophage cell line (RAW264.7) increased the levels of the Unc93b1 protein, whereas knockdown of p202 expression reduced the levels. To our knowledge, our observations demonstrate for the first time that activation of interferon and estrogen signaling in immune cells up-regulates the expression of murine Unc93b1.
内质网跨膜蛋白 Unc93b1 对于从内质网到内体的内体 TLR 的运输是必需的。人类 UNC93B1 基因的遗传缺陷与免疫缺陷有关。然而，红斑狼疮（SLE）患者的 B 细胞中 UNC93B1 蛋白表达水平增加。由于 SLE 患者和某些小鼠模型存在性别偏向，并且患者血清中 I 型干扰素水平升高与疾病活动相关，我们研究了雌性激素雌激素（E2）或 I 型干扰素信号是否可以上调小鼠 Unc93b1 基因的表达。我们发现，从 C57BL/6（B6）雌性而非同龄雄性分离的免疫细胞（CD3(+)，B220(+)，CD11b(+)和 CD11c(+)）中，Unc93b1 mRNA 和蛋白的稳态水平可测量地更高。此外，用 E2 或干扰素（IFN-α，IFN-β或 IFN-γ）处理 CD11b(+)和 B220(+)细胞显著增加了 Unc93b1 mRNA 和蛋白的水平。因此，免疫细胞中雌激素受体-α或 STAT1 表达的缺乏降低了 Unc93b1 蛋白的表达水平。有趣的是，与同龄 B6 雌性相比，B6.Nba2 狼疮易感雌性小鼠的 Unc93b1 蛋白水平明显更高。此外，在鼠巨噬细胞系（RAW264.7）中，干扰素和 E2 诱导的 p202 蛋白的表达增加增加了 Unc93b1 蛋白的水平，而 p202 表达的敲低则降低了水平。据我们所知，我们的观察结果首次表明，免疫细胞中干扰素和雌激素信号的激活可上调小鼠 Unc93b1 的表达。
