| First Author | Wang L | Year | 2013 |
| Journal | Stem Cells | Volume | 31 |
| Issue | 7 | Pages | 1383-95 |
| PubMed ID | 23553791 | Mgi Jnum | J:198357 |
| Mgi Id | MGI:5496463 | Doi | 10.1002/stem.1388 |
| Citation | Wang L, et al. (2013) IFN-gamma and TNF-alpha Synergistically Induce Mesenchymal Stem Cell Impairment and Tumorigenesis via NFkappaB Signaling. Stem Cells 31(7):1383-95 |
| abstractText | 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-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) synergistically impair self-renewal and differentiation of mesenchymal stem cells (MSCs) via nuclear factor kappaB (NFkappaB)-mediated activation of mothers against decapentaplegic homolog 7 (SMAD7) in ovariectomized (OVX) mice. More interestingly, a long-term elevated levels of IFN-gamma and TNF-alpha result in significantly increased susceptibility to malignant transformation in MSCs through NFkappaB-mediated upregulation of the oncogenes c-Fos and c-Myc. Depletion of either IFN-gamma or TNF-alpha in OVX mice abolishes MSC impairment and the tendency toward malignant transformation with no NFkappaB-mediated oncogene activation. Systemic administration of aspirin, which significantly reduces the levels of IFN-gamma and TNF-alpha, results in blockage of MSC deficiency and tumorigenesis by inhibition of NFkappaB/SMAD7 and NFkappaB/c-FOS and c-MYC pathways in OVX mice. In summary, this study reveals that inflammation factors, such as IFN-gamma and TNF-alpha, synergistically induce MSC deficiency via NFkappaB/SMAD7 signaling and tumorigenesis via NFkappaB-mediated oncogene activation. STEM Cells2013;31:1383-1395. |
