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.
Highlights
Caffeine (1,3,7-trimethylxanthine) is a purine alka loid present in the leaves, seeds or nuts of a number of plants and is consumed by many people worldwide on a daily basis due to its presence in tea or coffee
In line with our previous observations [10], we found that pro-inflammatory ligands of Tolllike receptors (TLRs) 2 (plasma membrane-associated TLR – 1 μg/ml peptidoglycan (PGN) was used as a ligand), 7/8 (endosomal TLRs recognising viral single-stranded RNA – 0.1 μg/ml resiquimod (R848) was employed as a ligand) induce activating S2448 phosphorylation of mammalian target of rapamycin (mTOR)
We found that neither THP-1 cells nor primary human leukocytes nor basophils contained the cytochrome P450 1A2 isoform which is primarily responsible for caffeine demethylation
Summary
Caffeine (1,3,7-trimethylxanthine) is a purine alka loid present in the leaves, seeds or nuts of a number of plants and is consumed by many people worldwide on a daily basis due to its presence in tea or coffee. For a long time caffeine was recognised as an isosteric inhibitor of cyclic adenosine monophosphate phosphodiesterase (cAMP-PDE) which upregulates intra cellular cAMP levels [2]. Caffeine was found to reduce the role of glycolysis in cell energy metabolism via upregulation of lipid degradation (lipolysis) [3, 4]. Recent evidence demonstrated that human hematopoietic cells do not express the cytochrome P450 1A2 isoform and should not be able to metabolise caffeine, resulting in the effects of unmodified caffeine [5]. In this case, caffeine could competitively inhibit www.impactjournals.com/oncotarget
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