Differential control of hypoxia-inducible factor 1 activity during pro-inflammatory reactions of human haematopoietic cells of myeloid lineage

Bernhard F Gibbs, Inna M Yasinska, Dmitri Pchejetski, Rafal W Wyszynski, Vadim V Sumbayev

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

The biological responses of human haematopoietic cells of myeloid lineage following malignant transformation depends crucially on their adaptation to signalling stress. This adaptation is dependent on the activation of the hypoxia-inducible factor 1 (HIF-1) transcription complex, although the mechanisms underlying its control remain unclear. Here, we report that mammalian target of rapamycin (mTOR) kinase, a central regulator of myeloid cell growth and metabolism, is crucially involved in HIF-1α accumulation/HIF-1 activation in human THP-1 myeloid monocytes, LAD2 mast cells and primary basophils in a variety of different settings. In THP-1 cells, mTOR was a major contributor to HIF-1 activation induced by ligands of both membrane-associated and endosomal toll-like receptors that recognise molecular patterns shared by pathogens. In LAD2 mast cells and primary human basophils mTOR was vital for HIF-1α accumulation/HIF-1 activity during immunoglobulin E (IgE)-dependent pro-allergic responses as well as in maintaining constitutive HIF-1α levels in mast cells. Furthermore, we observed that nitric oxide synthase activity was dependent on mTOR in these myeloid cells and involved in HIF-1α accumulation mediated by endosomal toll-like receptor 7/8 triggering in THP-1 cells as well as IgE-dependent basophil, but not mast cell, responses. In both cases the process is likely to be associated with an impact of reactive nitrogen species on HIF-1α-degrading prolyl hydroxylation. These studies underline the importance of mTOR as a fundamental regulator of HIF-1 signalling in myeloid cells.
Original languageEnglish
Pages (from-to)1739-49
Number of pages11
JournalInternational Journal of Biochemistry & Cell Biology
Volume44
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • Basophils
  • Cell Lineage
  • Congenital Disorders of Glycosylation
  • HEK293 Cells
  • Hematopoietic System
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Imidazoles
  • Inflammation
  • Myeloid Cells
  • Nitric Oxide Synthase
  • Peptidoglycan
  • Phosphorylation
  • Phosphoserine
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Toll-Like Receptors
  • Von Hippel-Lindau Tumor Suppressor Protein

Cite this