Interleukin-1 beta induces the expression and production of stem cell factor by epithelial cells： crucial involvement of the PI-3K/mTOR pathway and HIF-1 transcription complex  

作　　者：Rafal W Wyszynski Bernhard F Gibbs Luca Varani Daniela Iannotta Vadim V Sumbayev 

机构地区：[1]School of Pharmacy, University of Kent, Kent, UK [2]Institute for Research in Biomedicine, Bellinzona, Switzerland [3]These authors are Contributed equally to this study

出　　处：《Cellular & Molecular Immunology》2016年第1期47-56,共10页中国免疫学杂志（英文版）

摘　　要：Potential crosslinks between inflammation and leukaemia have been discussed for some time, but experimental evidence to support this dogma is scarce. In particular, it is important to understand the mechanisms responsible for potential upregulation of proto-oncogenic growth factor expressions by inflammatory mediators. Here, we investigated the ability of the highly inflammatory cytokine interleukin-1 beta （IL-1β） to induce the production of stem cell factor （SCF）, which is a major hematopoietic growth factor that controls the progression of acute myeloid leukaemia upon malignant transformation of haematopoietic myeloid cells. We found that human IL-1β induced the expression/secretion of SCF in MCF-7 human epithelial breast cancer cells and that this process depended on the hypoxia-inducible factor 1 （HIF-1） transcription complex. We also demonstrated a crucial role of the phosphatidylinositol-3 kinase （PI-3K）/mammalian target of rapamycin （mTOR） pathway in IL-1β-induced HIF-1α accumulation in MCF-7 cells. Importantly, mTOR was also found to play a role in IL-1β-induced SCF production. Furthermore, a tendency for a positive correlation of IL-1β and SCF levels in the plasma of healthy human donors was observed. Altogether, our results demonstrate that IL-1β, which normally bridges innate and adaptive immunity, induces the production of the major haematopoietic/proleukaemic growth factor SCF through the PI-3K/mTOR pathway and the HIF-1 transcription complex. These findings strongly suoDort a cross-talk between inflammation and acute mveloid leukaemia.Potential crosslinks between inflammation and leukaemia have been discussed for some time, but experimental evidence to support this dogma is scarce. In particular, it is important to understand the mechanisms responsible for potential upregulation of proto-oncogenic growth factor expressions by inflammatory mediators. Here, we investigated the ability of the highly inflammatory cytokine interleukin-1 beta （IL-1β） to induce the production of stem cell factor （SCF）, which is a major hematopoietic growth factor that controls the progression of acute myeloid leukaemia upon malignant transformation of haematopoietic myeloid cells. We found that human IL-1β induced the expression/secretion of SCF in MCF-7 human epithelial breast cancer cells and that this process depended on the hypoxia-inducible factor 1 （HIF-1） transcription complex. We also demonstrated a crucial role of the phosphatidylinositol-3 kinase （PI-3K）/mammalian target of rapamycin （mTOR） pathway in IL-1β-induced HIF-1α accumulation in MCF-7 cells. Importantly, mTOR was also found to play a role in IL-1β-induced SCF production. Furthermore, a tendency for a positive correlation of IL-1β and SCF levels in the plasma of healthy human donors was observed. Altogether, our results demonstrate that IL-1β, which normally bridges innate and adaptive immunity, induces the production of the major haematopoietic/proleukaemic growth factor SCF through the PI-3K/mTOR pathway and the HIF-1 transcription complex. These findings strongly suoDort a cross-talk between inflammation and acute mveloid leukaemia.

关 键 词：Inflammation Stem cell factor LEUKAEMIA HYPOXIA 

分 类 号：Q959.836[生物学—动物学] Q426