Wang, LeiZhao, YinghuaLiu, YiAkiyama, KentaroChen, ChiderQu, CunyeJin, YanShi, Songtao2023-05-222023-05-222013-07-012021-05-03https://repository.upenn.edu/handle/20.500.14332/8827An 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 NF-κB/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.This is the pre-peer reviewed version of the following article: [Wang, L., Zhao, Y., Liu, Y., Akiyama, K., Chen, C., Qu, C., . . . Shi, S. (2013). IFN‐γ and TNF‐α synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFκB signaling. Stem Cells, 31(7), 1383-1395. doi:10.1002/stem.1388]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Mesenchymal stem cellsStem cell-microenvironment interactionsDifferentiationCancerCytokinesDentistryArticle