IFN-? and TNF-? synergistically induce mesenchymal stem cell impairment and tumorigenesis via NF?B signaling.

ABSTRACT: 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-? (IFN-?) and tumor necrosis factor ? (TNF-?) synergistically impair self-renewal and differentiation of mesenchymal stem cells (MSCs) via nuclear factor ?B (NF?B)-mediated activation of mothers against decapentaplegic homolog 7 (SMAD7) in ovariectomized (OVX) mice. More interestingly, a long-term elevated levels of IFN-? and TNF-? result in significantly increased susceptibility to malignant transformation in MSCs through NF?B-mediated upregulation of the oncogenes c-Fos and c-Myc. Depletion of either IFN-? or TNF-? in OVX mice abolishes MSC impairment and the tendency toward malignant transformation with no NF?B-mediated oncogene activation. Systemic administration of aspirin, which significantly reduces the levels of IFN-? and TNF-?, results in blockage of MSC deficiency and tumorigenesis by inhibition of NF?B/SMAD7 and NF?B/c-FOS and c-MYC pathways in OVX mice. In summary, this study reveals that inflammation factors, such as IFN-? and TNF-?, synergistically induce MSC deficiency via NF?B/SMAD7 signaling and tumorigenesis via NF?B-mediated oncogene activation.

SUBMITTER: Wang L 

PROVIDER: S-EPMC3706580 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature