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

Gibbs, Bernhard F., Yasinska, Inna M., Pchejetski, Dmitri, Wyszynski, Rafal W., Sumbayev, Vadim V. (2012) Differential control of hypoxia-inducible factor 1 activity during pro-inflammatory reactions of human haematopoietic cells of myeloid lineage. International Journal of Biochemistry & Cell Biology, 44 (11). pp. 1739-1749. ISSN 1357-2725. (doi:10.1016/j.biocel.2012.06.019) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided)

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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-1? 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-1? accumulation/HIF-1 activity during immunoglobulin E (IgE)-dependent pro-allergic responses as well as in maintaining constitutive HIF-1? levels in mast cells. Furthermore, we observed that nitric oxide synthase activity was dependent on mTOR in these myeloid cells and involved in HIF-1? 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-1?-degrading prolyl hydroxylation. These studies underline the importance of mTOR as a fundamental regulator of HIF-1 signalling in myeloid cells.

Item Type: Article
DOI/Identification number: 10.1016/j.biocel.2012.06.019
Uncontrolled keywords: Hypoxia; Haematopoietic cells of myeloid lineage; Inflammation; Allergy; Mammalian target of rapamycin
Subjects: Q Science > QP Physiology (Living systems) > QP517 Biochemistry
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Vadim Sumbayev
Date Deposited: 08 Dec 2014 13:05 UTC
Last Modified: 29 May 2019 13:50 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/45790 (The current URI for this page, for reference purposes)
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