BACKGROUND: Mesenchymal stem cells (MSCs) can be efficiently recruited to wound, inflammatory and tumor sites to repair and regenerate tissue. However, its role in colitis and colitis associated colon cancer is still controversial. This study was designed to evaluate the role and mechanisms of inflammatory cytokines-activated-MSCs in mice colitis and colon cancer. METHODS: We selected two well-characterized pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), to expand the inflammatory microenvironment of MSCs. The severity of colitis and colon cancer was evaluated by measuring colon length, Myeloperoxidase (MPO) activity, Hematoxylin-eosin staining, Western Blot, Immunohistochemistry and Immunofluorescence. These techniques were also performed to analyze the mechanisms of inflammatory cytokines-activated-MSCs in mice colitis and colon cancer. Real-time PCR and Enzyme-linked Immunosorbent Assay (ELISA) were used to measure the secretion of pro-inflammatory factors. RESULTS: We found that the incubation of MSCs with TNF-α and IFN-γ aggravates colitis, where high levels of pro-inflammatory factors, such as interleukin (IL)-17, IL-8, IL-12, IL-1β, transforming growth factor (TGF)-β, TNF-α and IFN-γ, were secreted. Furthermore, this phenomenon was associated with the activation of the nuclear factor-kappa-B (NF-κB)/Signal transducer and activator of transcription three (STAT3) pathway. In addition, our study demonstrated that TNF-α and IFN-γ pretreated MSCs synergistically exacerbated mice colon cancer, which was closely associated with angiogenesis. CONCLUSIONS: Taken together, these results indicate that TNF-α and IFN-γ pretreatment effectively inhibited the repair ability of MSCs and accelerated inflammation and tumor progression involving NF-κB/STAT3 pathway and angiogenesis-related factors. AJTR
BACKGROUND: Mesenchymal stem cells (MSCs) can be efficiently recruited to wound, inflammatory and tumor sites to repair and regenerate tissue. However, its role in colitis and colitis associated colon cancer is still controversial. This study was designed to evaluate the role and mechanisms of inflammatory cytokines-activated-MSCs in micecolitis and colon cancer. METHODS: We selected two well-characterized pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), to expand the inflammatory microenvironment of MSCs. The severity of colitis and colon cancer was evaluated by measuring colon length, Myeloperoxidase (MPO) activity, Hematoxylin-eosin staining, Western Blot, Immunohistochemistry and Immunofluorescence. These techniques were also performed to analyze the mechanisms of inflammatory cytokines-activated-MSCs in micecolitis and colon cancer. Real-time PCR and Enzyme-linked Immunosorbent Assay (ELISA) were used to measure the secretion of pro-inflammatory factors. RESULTS: We found that the incubation of MSCs with TNF-α and IFN-γ aggravates colitis, where high levels of pro-inflammatory factors, such as interleukin (IL)-17, IL-8, IL-12, IL-1β, transforming growth factor (TGF)-β, TNF-α and IFN-γ, were secreted. Furthermore, this phenomenon was associated with the activation of the nuclear factor-kappa-B (NF-κB)/Signal transducer and activator of transcription three (STAT3) pathway. In addition, our study demonstrated that TNF-α and IFN-γ pretreated MSCs synergistically exacerbated micecolon cancer, which was closely associated with angiogenesis. CONCLUSIONS: Taken together, these results indicate that TNF-α and IFN-γ pretreatment effectively inhibited the repair ability of MSCs and accelerated inflammation and tumor progression involving NF-κB/STAT3 pathway and angiogenesis-related factors. AJTR
Authors: Florian R Greten; Lars Eckmann; Tim F Greten; Jin Mo Park; Zhi-Wei Li; Laurence J Egan; Martin F Kagnoff; Michael Karin Journal: Cell Date: 2004-08-06 Impact factor: 41.582