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Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity

Gibbs, Bernhard F., Gonçalves Silva, Isabel, Prokhorov, Alexandr, Abooali, Maryam, Yasinska, Inna M., Casely-Hayford, Maxwell A., Berger, Steffen M., Fasler-Kan, Elizaveta, Sumbayev, Vadim V. (2015) Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity. Oncotarget, 6 . pp. 28678-28692. ISSN 1949-2553. (doi:10.18632/oncotarget.5212) (KAR id:53267)

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Abstract

Correction of human myeloid cell function is crucial for the prevention of inflammatory and allergic reactions as well as leukaemia progression. Caffeine, a naturally occurring food component, is known to display anti-inflammatory effects which have previously been ascribed largely to its inhibitory actions on phosphodiesterase. However, more recent studies suggest an additional role in affecting the activity of the mammalian target of rapamycin (mTOR), a master regulator of myeloid cell translational pathways, although detailed molecular events underlying its mode of action have not been elucidated. Here, we report the cellular uptake of caffeine, without metabolisation, by healthy and malignant hematopoietic myeloid cells including monocytes, basophils and primary acute myeloid leukaemia mononuclear blasts. Unmodified caffeine downregulated mTOR signalling, which affected glycolysis and the release of pro-inflammatory/pro-angiogenic cytokines as well as other inflammatory mediators. In monocytes, the effects of caffeine were potentiated by its ability to inhibit xanthine oxidase, an enzyme which plays a central role in human purine catabolism by generating uric acid. In basophils, caffeine also increased intracellular cyclic adenosine monophosphate (cAMP) levels which further enhanced its inhibitory action on mTOR. These results demonstrate an important mode of pharmacological action of caffeine with potentially wide-ranging therapeutic impact for treating non-infectious disorders of the human immune system, where it could be applied directly to inflammatory cells.

Item Type: Article
DOI/Identification number: 10.18632/oncotarget.5212
Uncontrolled keywords: Medway School of Pharmacy
Subjects: Q Science
Divisions: Faculties > Sciences > Medway School of Pharmacy
Depositing User: Vadim Sumbayev
Date Deposited: 13 Dec 2015 16:42 UTC
Last Modified: 06 May 2020 03:13 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/53267 (The current URI for this page, for reference purposes)
Casely-Hayford, Maxwell A.: https://orcid.org/0000-0003-4054-4371
Sumbayev, Vadim V.: https://orcid.org/0000-0002-9404-5626
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