title: IFN-γ and TNF-α synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFκB 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-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.
authors.affiliation: University of Southern California, Los Angeles, CA, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Yinghua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Kentaro
authors.initials: K
authors.lastname: Akiyama
authors.forename: Chider
authors.initials: C
authors.lastname: Chen
authors.forename: Cunye
authors.initials: C
authors.lastname: Qu
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
authors.forename: Songtao
authors.initials: S
authors.lastname: Shi
mesh_terms: D000818:Animals; D001241:Aspirin / Q000494:pharmacology; D063646:Carcinogenesis; D002454:Cell Differentiation / Q000502:physiology; D005260:Female; D016762:Genes, fos; D016259:Genes, myc; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051906:Smad7 Protein / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D001241:Aspirin
keywords: Cancer; Cytokines; Differentiation; Mesenchymal stem cells; Stem cell-microenvironment interactions
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