IFN-γ and TNF-α Synergistically Induce Mesenchymal Stem Cell Impairment and Tumorigenesis via NFκB Signaling§

Authors

  • Lei Wang,

    1. Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
    2. Fourth Military Medical University School of Stomatology, Xi'an, China
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  • Yinghua Zhao,

    1. Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
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  • Yi Liu,

    1. Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
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  • Kentaro Akiyama,

    1. Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
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  • Chider Chen,

    1. Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
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  • Cunye Qu,

    1. Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
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  • Yan Jin,

    Corresponding author
    1. Fourth Military Medical University School of Stomatology, Xi'an, China
    • Department of Oral Histology and Pathology, School of Stomatology, 4th Military Medical University; 145 West Changle Road, Xi'an 710032, Shaanxi, China
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    • Telephone: 86-2984776147; Fax: +86-2983218039

  • Songtao Shi

    Corresponding author
    1. Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California, Los Angeles, California, USA
    • Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry, University of Southern California; 2250 Alcazar Street, CSA 103, Los Angeles, CA 90033, USA
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    • Telephone: +1-323-442-3038; Fax: +1-323-442-2981


  • Author contributions: S.S., Y.J. and L.W.: conception and design, writing manuscript, and final approval of manuscript; L.W., Y.Z., Y.L., K.A., C.C. and C.Q.: collection and assembly of data; S.S., L.W., Y.Z. and Y.L.: data analysis and interpretation.

  • Disclosure of potential conflicts of interest is found at the end of this article.

  • §

    first published online in STEM CELLS EXPRESS April 4, 2013.

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. STEM Cells2013;31:1383–1395

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