IFN-γ and TNF-α synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFκB signaling

Lei Wang, Yinghua Zhao, Yi Liu, Kentaro Akiyama, Chider Chen, Cunye Qu, Yan Jin, Songtao Shi

Research output: Contribution to journalArticle

83 Citations (Scopus)

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 jB (NFκB)-mediated activation of mothers against decapentaplegic homolog 7 (SMAD7) in ovariectomized (OVX) mice. More interestingly, a long-term elevated levels of IFN-c and TNF-α result in significantly increased susceptibility to malignant transformation in MSCs through NFκB-mediated upregulation of the oncogenes γ-Fos and γ-Myc. Depletion of either IFN-γ or TNF-a 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 γ-MYC pathways in OVX mice. In summary, this study reveals that inflammation factors, such as IFN-c and TNF-α, synergistically induce MSC deficiency via NFjB/SMAD7 signaling and tumorigenesis via NFκB-mediated oncogene activation.

Original languageEnglish
Pages (from-to)1383-1395
Number of pages13
JournalStem Cells
Volume31
Issue number7
DOIs
Publication statusPublished - Jul 1 2013
Externally publishedYes

Keywords

  • Cancer
  • Cytokines
  • Differentiation
  • Mesenchymal stem cells
  • Stem cell-microenvironment interactions

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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