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1.
PLoS One ; 12(9): e0183484, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28898256

RESUMO

Carbidopa is a drug that blocks conversion of levodopa to dopamine outside of central nervous system (CNS) and thus inhibits unwanted side effects of levodopa on organs located outside of CNS during management of Parkinson's Disease (PD). PD is associated with increased expression of inflammatory genes in peripheral and central nervous system (CNS), infiltration of immune cells into brain, and increased numbers of activated/memory T cells. Animal models of PD have shown a critical role of T cells in inducing pathology in CNS. However, the effect of carbidopa on T cell responses in vivo is unknown. In this report, we show that carbidopa strongly inhibited T cell activation in vitro and in vivo. Accordingly, carbidopa mitigated myelin oligodendrocyte glycoprotein peptide fragment 35-55 (MOG-35-55) induced experimental autoimmune encephalitis (EAE) and collagen induced arthritis in animal models. The data presented here suggest that in addition to blocking peripheral conversion of levodopa, carbidopa may inhibit T cell responses in PD individuals and implicate a potential therapeutic use of carbidopa in suppression of T cell mediated pathologies.


Assuntos
Antiparkinsonianos/farmacologia , Autoimunidade/efeitos dos fármacos , Carbidopa/farmacologia , Dopaminérgicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Animais , Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/metabolismo
2.
Biochem J ; 469(2): 267-78, 2015 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25984582

RESUMO

Mammalian colon harbours trillions of bacteria under physiological conditions; this symbiosis is made possible because of a tolerized response from the mucosal immune system. The mechanisms underlying this tolerogenic phenomenon remain poorly understood. In the present study we show that Slc5a8 (solute carrier gene family 5a, member 8), a Na(+)-coupled high-affinity transporter in colon for the bacterial fermentation product butyrate, plays a critical role in this process. Among various immune cells in colon, dendritic cells (DCs) are unique not only in their accessibility to luminal contents but also in their ability to induce tolerogenic phenotype in T-cells. We found that DCs exposed to butyrate express the immunosuppressive enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and aldehyde dehydrogenase 1A2 (Aldh1A2), promote conversion of naive T-cells into immunosuppressive forkhead box P3(+) (FoxP3(+)) Tregs (regulatory T-cells) and suppress conversion of naive T-cells into pro-inflammatory interferon (IFN)-γ-producing cells. Slc5a8-null DCs do not induce IDO1 and Aldh1A2 and do not generate Tregs or suppress IFN-γ-producing T-cells in response to butyrate. We also provide in vivo evidence for an obligatory role for Slc5a8 in suppression of IFN-γ-producing T-cells. Furthermore, Slc5a8 protects against colitis and colon cancer under conditions of low-fibre intake but not when dietary fibre intake is optimal. This agrees with the high-affinity nature of the transporter to mediate butyrate entry into cells. We conclude that Slc5a8 is an obligatory link between dietary fibre and mucosal immune system via the bacterial metabolite butyrate and that this transporter is a conditional tumour suppressor in colon linked to dietary fibre content.


Assuntos
Proteínas de Transporte de Cátions/imunologia , Colite/imunologia , Colo/imunologia , Neoplasias do Colo/imunologia , Fibras na Dieta/farmacologia , Imunidade nas Mucosas , Proteínas Supressoras de Tumor/imunologia , Aldeído Desidrogenase/genética , Aldeído Desidrogenase/imunologia , Família Aldeído Desidrogenase 1 , Animais , Ácido Butírico/farmacologia , Proteínas de Transporte de Cátions/genética , Colite/genética , Colite/patologia , Colo/patologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Células Dendríticas/imunologia , Células Dendríticas/patologia , Ácidos Graxos/genética , Ácidos Graxos/imunologia , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Antagonistas dos Receptores Histamínicos/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Tolerância Imunológica/genética , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Indolamina-Pirrol 2,3,-Dioxigenase/imunologia , Interferon gama/genética , Interferon gama/imunologia , Camundongos , Camundongos Knockout , Transportadores de Ácidos Monocarboxílicos , Retinal Desidrogenase , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Proteínas Supressoras de Tumor/genética
3.
Immunity ; 40(1): 128-39, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24412617

RESUMO

Commensal gut microflora and dietary fiber protect against colonic inflammation and colon cancer through unknown targets. Butyrate, a bacterial product from fermentation of dietary fiber in the colon, has been implicated in this process. GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing T cells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 in colonic epithelium. Consequently, Niacr1(-/-) mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr10a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon.


Assuntos
Carcinogênese/imunologia , Colite/imunologia , Colo/imunologia , Neoplasias do Colo/prevenção & controle , Células Epiteliais/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Butiratos/imunologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Colite/complicações , Colite/tratamento farmacológico , Colo/microbiologia , Colo/patologia , Neoplasias do Colo/etiologia , Células Dendríticas/imunologia , Suscetibilidade a Doenças , Células Epiteliais/efeitos dos fármacos , Interleucina-10/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microbiota , Niacina/administração & dosagem , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Receptores Nicotínicos/genética , Receptores Nicotínicos/imunologia , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia
4.
J Biol Chem ; 286(36): 31830-8, 2011 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-21771784

RESUMO

SLC6A14, also known as ATB(0,+), is an amino acid transporter with unique characteristics. It transports 18 of the 20 proteinogenic amino acids. However, this transporter is expressed only at low levels in normal tissues. Here, we show that the transporter is up-regulated specifically in estrogen receptor (ER)-positive breast cancer, demonstrable with primary human breast cancer tissues and human breast cancer cell lines. SLC6A14 is an estrogen/ER target. The transport features of SLC6A14 include concentrative transport of leucine (an activator of mTOR), glutamine (an essential amino acid for nucleotide biosynthesis and substrate for glutaminolysis), and arginine (an essential amino acid for tumor cells), suggesting that ER-positive breast cancer cells up-regulate SLC6A14 to meet their increased demand for these amino acids. Consequently, treatment of ER-positive breast cancer cells in vitro with α-methyl-DL-tryptophan (α-MT), a selective blocker of SLC6A14, induces amino acid deprivation, inhibits mTOR, and activates autophagy. Prolongation of the treatment with α-MT causes apoptosis. Addition of an autophagy inhibitor (3-methyladenine) during α-MT treatment also induces apoptosis. These effects of α-MT are specific to ER-positive breast cancer cells, which express the transporter. The ability of α-MT to cause amino acid deprivation is significantly attenuated in MCF-7 cells, an ER-positive breast cancer cell line, when SLC6A14 is silenced with shRNA. In mouse xenograft studies, α-MT by itself is able to reduce the growth of the ER-positive ZR-75-1 breast cancer cells. These studies identify SLC6A14 as a novel and effective drug target for the treatment of ER-positive breast cancer.


Assuntos
Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inibidores , Neoplasias da Mama/tratamento farmacológico , Sistemas de Transporte de Aminoácidos , Sistemas de Transporte de Aminoácidos Neutros/genética , Animais , Autofagia/efeitos dos fármacos , Neoplasias da Mama/patologia , Feminino , Humanos , Camundongos , Terapia de Alvo Molecular/métodos , Receptores de Estrogênio , Transplante Heterólogo , Triptofano/análogos & derivados , Triptofano/farmacologia , Células Tumorais Cultivadas
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