Involvement of hypoxia-inducible factor-1 HiF(1alpha) in IgE-mediated primary human basophil responses.
Basophils play a pivotal role in regulating chronic allergic inflammation as well as angiogenesis. Here, we show for the first time that IgE-mediated activation of primary human basophils results in protein accumulation of the alpha-subunit of hypoxia-inducible factor 1alpha (HIF-1alpha), which is differentially regulated compared with signals controlling histamine release. HIF-1 facilitates cellular adaptation to hypoxic conditions such as inflammation and tumour growth by controlling glycolysis, angiogenesis and cell adhesion. ERK and p38 MAPK, but not reactive oxygen species (ROS), ASK1 or PI 3-kinase, were critical for IgE-mediated accumulation of HIF-1alpha, although the latter crucially affected degranulation. Abrogating HIF-1alpha expression in basophils using siRNA demonstrated that this protein is essential for vascular endothelial growth factor (VEGF) mRNA expression and, consequently, release of VEGF protein. In addition, HIF-1alpha protein alters IgE-induced ATP depletion in basophils, thus also supporting the production of the pro-allergic cytokine IL-4.
Sumbayev
Vadim V
VV
Medway School of Pharmacy, University of Kent, Chatham Maritime, Kent, UK. V.Sumbayev@kent.ac.uk
Nicholas
Sally A
SA
Streatfield
Claire L
CL
Gibbs
Bernhard F
BF
D000255:Adenosine Triphosphate / Q000378:metabolism; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology / Q000494:pharmacology; D001491:Basophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007073:Immunoglobulin E / Q000276:immunology*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000888:Antibodies, Anti-Idiotypic; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C026408:anti-IgE antibodies; D015847:Interleukin-4; D007073:Immunoglobulin E; D000255:Adenosine Triphosphate; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases