61 Hypoxia-Inducible Factor 1 (HIF-1) Transcription is a “Signalling Driver” for Allergic Inflammation, Host Innate Immune Defence and Leukaemia Progression

Abstract

BackgroundHypoxia-inducible factor 1 is a transcription complex that plays a pivotal role in cellular adaptation to low oxygen availability, which occurs during allergic responses, host immune defence and leukaemia progression. We investigated the role of HIF-1 in cellular adaptation to stress associated with different types of pathological reactions of immune cells. We studied IgE-dependent responses of human mast cells and basophils, Toll-like receptor (TLR)-mediated innate immune reactions of human myeloid cells and stem cell factor (SCF)-mediated responses of hematopoietic cells of myeloid lineage.MethodsLAD2 human mast cells1, primary human basophils, and THP-1 human myeloid cells were used for investigations of FcεRI, TLR ligand and SCF-induced responses. Quantitative real-time PCR, Western blot analysis, ELISA, fluorometry, luminometry and fluorescence microscopy were employed to run the assays.ResultsWe observed that HIF-1 activation is differentially regulated in the cases of pro-allergic, TLR-dependent and SCF-induced cellular responses. While PI3K/mTOR and MAP kinase pathways were the major contributors to HIF-1 activation during allergic/SCF-dependent responses, TLR-mediated processes occurred mostly via redox-dependent mechanisms. Experiments with HIF-1α (the inducible subunit regulating HIF-1 transactivation) knockdown cells demonstrated that HIF-1 plays a crucial role in the expression of the primary angiogenic cytokine VEGF and controls intracellular energy metabolism by regulating glycolytic metabolic activity.ConclusionsThe HIF-1 transcription complex supports not only the survival of immune cells (mast cells, basophils, myeloid cells) in pathological environments but also determines their abilities to generate pro-allergic, pro-inflammatory as well as pro-angiogenic cytokines over sustained periods.