University of Southern California, Los Angeles, CA, USA.
Stem Cells. 2013 Jul;31(7):1383-95. doi: 10.1002/stem.1388.
An inflammatory microenvironment may cause organ degenerative diseases and malignant tumors. However, the precise mechanisms of inflammation-induced diseases are not fully understood. Here, we show that the proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α) synergistically impair self-renewal and differentiation of mesenchymal stem cells (MSCs) via nuclear factor κB (NFκB)-mediated activation of mothers against decapentaplegic homolog 7 (SMAD7) in ovariectomized (OVX) mice. More interestingly, a long-term elevated levels of IFN-γ and TNF-α result in significantly increased susceptibility to malignant transformation in MSCs through NFκB-mediated upregulation of the oncogenes c-Fos and c-Myc. Depletion of either IFN-γ or TNF-α in OVX mice abolishes MSC impairment and the tendency toward malignant transformation with no NFκB-mediated oncogene activation. Systemic administration of aspirin, which significantly reduces the levels of IFN-γ and TNF-α, results in blockage of MSC deficiency and tumorigenesis by inhibition of NFκB/SMAD7 and NFκB/c-FOS and c-MYC pathways in OVX mice. In summary, this study reveals that inflammation factors, such as IFN-γ and TNF-α, synergistically induce MSC deficiency via NFκB/SMAD7 signaling and tumorigenesis via NFκB-mediated oncogene activation.
炎症微环境可能导致器官退行性疾病和恶性肿瘤。然而，炎症诱导疾病的确切机制尚不完全清楚。在这里，我们表明促炎细胞因子干扰素-γ (IFN-γ) 和肿瘤坏死因子-α (TNF-α) 通过核因子 κB (NFκB) 介导的母系抗狄氏蛋白同源物 7 (SMAD7) 的激活协同损害卵巢切除 (OVX) 小鼠间充质干细胞 (MSC) 的自我更新和分化。更有趣的是，IFN-γ 和 TNF-α 的长期高水平导致 MSC 中致癌基因 c-Fos 和 c-Myc 的 NFκB 介导的上调导致恶性转化的易感性显著增加。在 OVX 小鼠中耗尽 IFN-γ 或 TNF-α 会消除 MSC 损伤和恶性转化的趋势，而不会激活 NFκB 介导的致癌基因。阿司匹林的全身给药可显著降低 IFN-γ 和 TNF-α 的水平，通过抑制 NFκB/SMAD7 和 NFκB/c-FOS 和 c-MYC 通路，阻断 OVX 小鼠 MSC 缺乏和肿瘤发生。总之，这项研究揭示了炎症因子，如 IFN-γ 和 TNF-α，通过 NFκB/SMAD7 信号协同诱导 MSC 缺陷，并通过 NFκB 介导的致癌基因激活诱导肿瘤发生。
