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1.
Oncotarget ; 6(30): 28678-92, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26384306

RESUMO

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.


Assuntos
Cafeína/farmacologia , Linhagem da Célula , Células Mieloides/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Xantina Oxidase/metabolismo , Proteínas Angiogênicas/metabolismo , Basófilos/efeitos dos fármacos , Basófilos/enzimologia , Cafeína/metabolismo , Linhagem Celular Tumoral , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Regulação para Baixo , Glicólise/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Monócitos/efeitos dos fármacos , Monócitos/enzimologia , Células Mieloides/enzimologia , Células Mieloides/patologia , Transdução de Sinais/efeitos dos fármacos
2.
Int J Biochem Cell Biol ; 59: 11-20, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25483439

RESUMO

The T-cell immunoglobulin and mucin domain 3 (Tim-3) is a plasma membrane-associated protein that is highly expressed in human acute myeloid leukaemia cells. As an acute myeloid leukaemia antigen, it could therefore be considered as a potential target for immune therapy and highly-specific drug delivery. However, a conceptual understanding of its biological role is required before consideration of this protein for therapeutic settings. Here, we reveal the detailed mechanism of action underlying the biological responses mediated by the Tim-3 receptor in myeloid cells. Our studies demonstrate that Tim-3 triggers growth factor type responses in acute myeloid leukaemia cells by activating a phosphatidylinositol-3 kinase (PI-3K)/mammalian target of rapamycin (mTOR) pathway. In addition, the receptor activates hypoxic signalling pathways upregulating glycolysis and pro-angiogenic responses. These findings suggest that Tim-3 could be used as a potential therapeutic target for immune therapy and drug delivery in human acute myeloid leukaemia cells.


Assuntos
Fator 1 Induzível por Hipóxia/metabolismo , Leucemia Mieloide/metabolismo , Proteínas de Membrana/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Cálcio/metabolismo , Linhagem Celular Tumoral , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Galectinas/metabolismo , Receptor Celular 2 do Vírus da Hepatite A , Humanos , Leucemia Mieloide/enzimologia , Leucemia Mieloide/patologia , Ligantes , Proteínas de Membrana/química , Modelos Biológicos , Fosforilação , Fosfosserina/metabolismo , Fosfotirosina/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Fator de Células-Tronco/metabolismo , Fatores de Tempo , Fosfolipases Tipo C/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
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