Open AccessIFN‐γ and TNF‐α Synergistically Induce Mesenchymal Stem Cell Impairment and Tumorigenesis via NFκB Signaling
Author(s) -
Wang Lei,
Zhao Yinghua,
Liu Yi,
Akiyama Kentaro,
Chen Chider,
Qu Cunye,
Jin Yan,
Shi Songtao
Publication year - 2013
Publication title -
stem cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.159
H-Index - 229
eISSN - 1549-4918
pISSN - 1066-5099
DOI - 10.1002/stem.1388
Subject(s) - biology , proinflammatory cytokine , tumor necrosis factor alpha , nf κb , carcinogenesis , cancer research , oncogene , mesenchymal stem cell , downregulation and upregulation , inflammation , nfkb1 , stem cell , immunology , signal transduction , microbiology and biotechnology , cell , transcription factor , cell cycle , cancer , biochemistry , genetics , gene
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. S TEM C ells 2013;31:1383–1395