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

72 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 2013
Externally publishedYes

Fingerprint

Mesenchymal Stromal Cells
Interferons
Carcinogenesis
Oncogenes
Smad Proteins
Inflammation
Aspirin
Up-Regulation
Tumor Necrosis Factor-alpha
Cytokines
Neoplasms

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Developmental Biology
  • Molecular Medicine

Cite this

IFN-γ and TNF-α synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFκB signaling. / Wang, Lei; Zhao, Yinghua; Liu, Yi; Akiyama, Kentaro; Chen, Chider; Qu, Cunye; Jin, Yan; Shi, Songtao.

In: Stem Cells, Vol. 31, No. 7, 07.2013, p. 1383-1395.

Research output: Contribution to journalArticle

Wang, Lei ; Zhao, Yinghua ; Liu, Yi ; Akiyama, Kentaro ; Chen, Chider ; Qu, Cunye ; Jin, Yan ; Shi, Songtao. / IFN-γ and TNF-α synergistically induce mesenchymal stem cell impairment and tumorigenesis via NFκB signaling. In: Stem Cells. 2013 ; Vol. 31, No. 7. pp. 1383-1395.
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