title: 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.
abstract: 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 support a cross-talk between inflammation and acute myeloid leukaemia.
authors.affiliation: School of Pharmacy, University of Kent, Kent, UK.
authors.forename: Rafal W
authors.initials: RW
authors.lastname: Wyszynski
authors.affiliation: School of Pharmacy, University of Kent, Kent, UK.
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gibbs
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.
authors.forename: Luca
authors.initials: L
authors.lastname: Varani
authors.affiliation: Institute for Research in Biomedicine, Bellinzona, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Iannotta
authors.affiliation: School of Pharmacy, University of Kent, Kent, UK.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
mesh_terms: D056704:Adaptive Immunity; D015687:Cell Hypoxia; D002460:Cell Line; D003001:Cloning, Molecular; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000276:immunology*; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D061986:MCF-7 Cells; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000235:genetics / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053583:Interleukin-1beta; D019869:Phosphatidylinositol 3-Kinases; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D058570:TOR Serine-Threonine Kinases; C497442:HIF1A protein, human; C546842:MTOR protein, human