During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2. However, in this study, the constitutive expression of ISGs in human-derived senescent fibroblasts and in fibroblasts from a patient with Werner syndrome, which leads to premature aging, was mediated mainly by the unphosphorylated forms of STATs in the absence of INF production. Under homeostatic conditions, STAT1, STAT2, and IRF9 were localized to the nucleus of aged cells. Although knockdown of JAK1, a key kinase of STAT1 and STAT2, did not affect ISG expression or IFN-stimulated response element (ISRE)-mediated promoter activities in these senescent cells, knockdown of STAT1 or STAT2 decreased ISG expression and ISRE activities. These results suggest that the ISGF3 complex without clear phosphorylation is required for IFN-independent constitutive ISG transcription in senescent cells.

在细胞衰老期间，细胞功能发生许多变化。衰老细胞的标志是炎性介质的分泌，其统称为衰老相关的分泌表型（SASP）。但是，这种变化的潜在机制尚不清楚。规范地说，干扰素（IFN）刺激基因（ISGs）的表达是由IFN通过形成三重转录因子ISGF3（由IRF9以及STAT1和STAT2的磷酸化形式组成）诱导的。然而，在这项研究中，ISG在人源性衰老成纤维细胞和Werner综合征患者的成纤维细胞中的组成型表达，导致过早衰老，主要是由STAT的非磷酸化形式介导的，而没有INF的产生。在稳态条件下，STAT1，STAT2，IRF9和IRF9定位于衰老细胞的细胞核。虽然敲低STAT1和STAT2的关键激酶JAK1不会影响这些衰老细胞中ISG的表达或IFN刺激的响应元件（ISRE）介导的启动子活性，但STAT1或STAT2的敲低会降低ISG表达和ISRE活性。这些结果表明，衰老细胞中不依赖IFN的组成型ISG转录需要没有明显磷酸化的ISGF3复合物。