title: Caffeine affects the biological responses of human hematopoietic cells of myeloid lineage via downregulation of the mTOR pathway and xanthine oxidase activity.
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.
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Gibbs
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Isabel
authors.initials: I
authors.lastname: Gonçalves Silva
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Alexandr
authors.initials: A
authors.lastname: Prokhorov
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Maryam
authors.initials: M
authors.lastname: Abooali
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Inna M
authors.initials: IM
authors.lastname: Yasinska
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Maxwell A
authors.initials: MA
authors.lastname: Casely-Hayford
authors.affiliation: Department of Pediatric Surgery and Department of Clinical Research, Inselspital, University Hospital, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Steffen M
authors.initials: SM
authors.lastname: Berger
authors.affiliation: Department of Pediatric Surgery and Department of Clinical Research, Inselspital, University Hospital, University of Bern, CH-3010 Bern, Switzerland.|Department of Biomedicine, University of Basel and University Hospital Basel, CH-4031 Basel, Switzerland.
authors.forename: Elizaveta
authors.initials: E
authors.lastname: Fasler-Kan
authors.affiliation: School of Pharmacy, University of Kent, Chatham Maritime, ME4 4TB Kent, United Kingdom.
authors.forename: Vadim V
authors.initials: VV
authors.lastname: Sumbayev
mesh_terms: D042501:Angiogenic Proteins / Q000378:metabolism; D001491:Basophils / Q000187:drug effects / Q000201:enzymology; D002110:Caffeine / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019070:Cell Lineage; D016207:Cytokines / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D022423:Myeloid Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014969:Xanthine Oxidase / Q000378:metabolism*
chemical_list: D042501:Angiogenic Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D002110:Caffeine; D014969:Xanthine Oxidase; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Immune response; Immunity; Immunology and Microbiology Section; allergy; caffeine; inflammation; myeloid cells