title: Involvement of hypoxia-inducible factor-1 in the inflammatory responses of human LAD2 mast cells and basophils.
abstract: We recently showed that hypoxia-inducible factor 1 (HIF-1) plays a crucial role in the pro-allergic functions of human basophils by transcriptional control of energy metabolism via glycolysis as well as directly triggering expression of the angiogenic cytokine vascular endothelium growth factor (VEGF). Here, we investigated HIF-1 involvement in controlling the synthesis of angiogenic and inflammatory cytokines from various human effector cells stimulated by IgE-dependent or innate immune triggers. Purified primary human basophils, LAD2 human mast cells and THP-1 human myeloid cells were used for investigations of FcεRI and Toll-like receptor (TLR) ligand-induced responses. In contrast to basophils, LAD2 mast cells expressed background levels of HIF-1α, which was largely independent of the effects of stem cell factor (SCF). Both mast cells and basophils expressed TLR2 and 4, albeit weakly compared to THP-1 cells. Cytokine production in mast cells following TLR ligand stimulation was markedly reduced by HIF-1α knockdown in LAD2 mast cells. In contrast, although HIF-1 is involved in IgE-mediated IL-4 secretion from basophils, it is not clearly induced by peptidoglycan (PGN). HIF-1α accumulation is critical for sustaining human allergic effector cell survival and function. This transcription complex facilitates generation of both pro-angiogenic and inflammatory cytokines in mast cells but has a differential role in basophil stimulation comparing IgE-dependent triggering with innate immune stimuli.
authors.affiliation: Medway School of Pharmacy, University of Kent, Chatham Maritime, United Kingdom. V.Sumbayev@kent.ac.uk
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
authors.forename: Inna
authors.initials: I
authors.lastname: Yasinska
authors.forename: Abraham E
authors.initials: AE
authors.lastname: Oniku
authors.forename: Claire L
authors.initials: CL
authors.lastname: Streatfield
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gibbs
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D001491:Basophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007113:Immunity, Innate; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010457:Peptidoglycan / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D019089:Stem Cell Factor / Q000494:pharmacology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008024:Ligands; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D019089:Stem Cell Factor; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D042461:Vascular Endothelial Growth Factor A