RESUMO
BACKGROUND: Metabolic reprogramming plays an essential role on lymphoma progression. Dysregulation of glutamine metabolism is implicated in natural-killer T-cell lymphoma (NKTCL) and tumor cell response to asparaginase-based anti-metabolic treatment. METHODS: To understand the metabolomic alterations and determine the potential therapeutic target of asparaginase, we assessed metabolomic profile using liquid chromatography-mass spectrometry in serum samples of 36 NKTCL patients, and integrated targeted metabolic analysis and RNA sequencing in tumor samples of 102 NKTCL patients. The biological function of solute carrier family 1 member 1 (SLC1A1) on metabolic flux, lymphoma cell growth, and drug sensitivity was further examined in vitro in NK-lymphoma cell line NK-92 and SNK-6, and in vivo in zebrafish xenograft models. FINDINGS: In NKTCL patients, serum metabolomic profile was characterized by aberrant glutamine metabolism and SLC1A1 was identified as a central regulator of altered glutaminolysis. Both in vitro and in vivo, ectopic expression of SLC1A1 increased cellular glutamine uptake, enhanced glutathione metabolic flux, and induced glutamine addiction, leading to acceleration of cell proliferation and tumor growth. Of note, SLC1A1 overexpression was significantly associated with PD-L1 downregulation and reduced cytotoxic CD3+/CD8+ T cell activity when co-cultured with peripheral blood mononuclear cells. Asparaginase treatment counteracted SLC1A1-mediated glutamine addiction, restored SLC1A1-induced impaired T-cell immunity. Clinically, high EAAT3 (SLC1A1-encoded protein) expression independently predicted superior progression-free and overall survival in 90 NKTCL patients treated with asparaginase-based regimens. INTERPRETATION: SLC1A1 functioned as an extracellular glutamine transporter, promoted tumor growth through reprogramming glutamine metabolism of NKTCL, while rendered tumor cells sensitive to asparaginase treatment. Moreover, SLC1A1-mediated modulation of PD-L1 expression might provide clinical rationale of co-targeting metabolic vulnerability and immunosuppressive microenvironment in NKTCL. FUNDING: This study was supported, in part, by research funding from the National Natural Science Foundation of China (82130004, 81830007 and 81900192), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Shanghai Chenguang Program (19CG15), Shanghai Sailing Program (19YF1430800), Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (ZH2018QNA46), and Shanghai Yi Yuan Xin Xing Program.
Assuntos
Transportador 3 de Aminoácido Excitatório/metabolismo , Glutamina/imunologia , Linfoma Extranodal de Células T-NK/metabolismo , Células T Matadoras Naturais/metabolismo , Animais , Asparaginase/imunologia , Asparaginase/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Proliferação de Células/fisiologia , Regulação para Baixo/imunologia , Transportador 3 de Aminoácido Excitatório/imunologia , Feminino , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Linfoma Extranodal de Células T-NK/imunologia , Linfoma Extranodal de Células T-NK/terapia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Peixe-ZebraRESUMO
Macrophages represent the first line of defence in innate immune responses and additionally serve important functions for the regulation of host inflammation and tissue homeostasis. The M1/M2 model describes the two extremes of macrophage polarization states, which can be induced by multiple stimuli, most notably by LPS/IFN-γ and IL-4/IL-13. Historically, the expression of two genes encoding for enzymes, which use the same amino acid as their substrate, iNOS and ARG1, has been used to define classically activated M1 (iNOS) and alternatively activated M2 (ARG1) macrophages. This 'arginine dichotomy' has recently become a matter of debate; however, in parallel with the emerging field of immunometabolism there is accumulating evidence that these two enzymes and their related metabolites are fundamentally involved in the intrinsic regulation of macrophage polarization and function. The aim of this review is to highlight recent advances in macrophage biology and immunometabolism with a specific focus on amino acid metabolism and their related metabolic pathways: iNOS/ARG1 (arginine), TCA cycle and OXPHOS (glutamine) as well as the one-carbon metabolism (serine, glycine).
Assuntos
Arginase/metabolismo , Arginina/metabolismo , Glutamina/metabolismo , Glicina/imunologia , Macrófagos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Serina/metabolismo , Arginase/genética , Arginase/imunologia , Arginina/imunologia , Diferenciação Celular/efeitos dos fármacos , Ciclo do Ácido Cítrico/genética , Ciclo do Ácido Cítrico/imunologia , Regulação da Expressão Gênica , Glutamina/imunologia , Glicina/metabolismo , Humanos , Imunidade Inata , Interferon gama/farmacologia , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/classificação , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Óxido Nítrico/imunologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Fosforilação Oxidativa , Serina/imunologiaRESUMO
Rapidly proliferating tumor and immune cells need metabolic programs that support energy and biomass production. The amino acid glutamine is consumed by effector T cells and glutamine-addicted triple-negative breast cancer (TNBC) cells, suggesting that a metabolic competition for glutamine may exist within the tumor microenvironment, potentially serving as a therapeutic intervention strategy. Here, we report that there is an inverse correlation between glutamine metabolic genes and markers of T cell-mediated cytotoxicity in human basal-like breast cancer (BLBC) patient data sets, with increased glutamine metabolism and decreased T cell cytotoxicity associated with poor survival. We found that tumor cell-specific loss of glutaminase (GLS), a key enzyme for glutamine metabolism, improved antitumor T cell activation in both a spontaneous mouse TNBC model and orthotopic grafts. The glutamine transporter inhibitor V-9302 selectively blocked glutamine uptake by TNBC cells but not CD8+ T cells, driving synthesis of glutathione, a major cellular antioxidant, to improve CD8+ T cell effector function. We propose a "glutamine steal" scenario, in which cancer cells deprive tumor-infiltrating lymphocytes of needed glutamine, thus impairing antitumor immune responses. Therefore, tumor-selective targeting of glutamine metabolism may be a promising therapeutic strategy in TNBC.
Assuntos
Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Transporte/antagonistas & inibidores , Glutamina/imunologia , Imunidade Celular , Linfócitos do Interstício Tumoral/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Proteínas de Transporte/imunologia , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Feminino , Glutamina/metabolismo , Xenoenxertos , Humanos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Camundongos , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Myeloid cells comprise a major component of the tumor microenvironment (TME) that promotes tumor growth and immune evasion. By employing a small-molecule inhibitor of glutamine metabolism, not only were we able to inhibit tumor growth, but we markedly inhibited the generation and recruitment of myeloid-derived suppressor cells (MDSCs). Targeting tumor glutamine metabolism led to a decrease in CSF3 and hence recruitment of MDSCs as well as immunogenic cell death, leading to an increase in inflammatory tumor-associated macrophages (TAMs). Alternatively, inhibiting glutamine metabolism of the MDSCs themselves led to activation-induced cell death and conversion of MDSCs to inflammatory macrophages. Surprisingly, blocking glutamine metabolism also inhibited IDO expression of both the tumor and myeloid-derived cells, leading to a marked decrease in kynurenine levels. This in turn inhibited the development of metastasis and further enhanced antitumor immunity. Indeed, targeting glutamine metabolism rendered checkpoint blockade-resistant tumors susceptible to immunotherapy. Overall, our studies define an intimate interplay between the unique metabolism of tumors and the metabolism of suppressive immune cells.
Assuntos
Imunidade Celular , Macrófagos/imunologia , Células Supressoras Mieloides/imunologia , Neoplasias Experimentais/imunologia , Microambiente Tumoral/imunologia , Animais , Feminino , Glutamina/imunologia , Imunoterapia , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Supressoras Mieloides/patologia , Neoplasias Experimentais/patologia , Neoplasias Experimentais/terapiaRESUMO
The only generally accepted treatment of coeliac disease (CD) is a lifelong gluten-free diet. Wheat gluten proteins include gliadins, low and high molecular weight glutenins. However, we have found significant structural variations within these protein families among different cultivars. To determine which structural motifs might be less toxic than others, we assessed five variants of α-gliadin immunodominant CD-toxic peptides synthesised as 16mers in CD T cell stimulation assays with gluten-sensitive T cell lines generated from duodenal biopsies from CD-affected individuals. The peptides harboured the overlapping T cell epitopes DQ 2.5-glia-α-2 and naturally occurring variants that differed in certain amino acids (AA). The results revealed that introduction of two selected AA substitutions in α-gliadin peptides reduced immunogenicity. A peptide with three AA substitutions involving two glutamic acids (E) and one glutamine residue (G) revealed the peptide was negative in 5:5 samples. We used CD small-intestinal organ culture to assess CD toxicity that revealed two peptides with selected substitution of both glutamic acid (E) and proline (P) residues abrogated evidence of CD toxicity.
Assuntos
Doença Celíaca/imunologia , Gliadina/imunologia , Glutens/imunologia , Peptídeos/imunologia , Triticum/química , Aminoácidos , Duodeno/imunologia , Ácido Glutâmico/imunologia , Glutamina/imunologia , Humanos , Fenômenos Imunogenéticos , Prolina/imunologia , Linfócitos T/imunologiaRESUMO
Tumor-associated myeloid cells are one of the prominent components of solid tumors, serving as major immune regulators for the tumor microenvironment (TME) and an obstacle for immune-checkpoint blocking (ICB) therapy. However, it remains unclear how metabolic processes regulate the generation of suppressive myeloid cells in the TME. Here, we found that hematopoietic precursor cells are enriched in the tissues of several types of human cancer and can differentiate into immature myeloid cells (IMC). Tumor-infiltrating IMCs are highly immunosuppressive, glycolytic, and proliferative, as indicated by high levels of M-CSFR, Glut1, and Ki67. To elucidate the role of metabolism in regulating the generation of IMCs, we induced suppressive IMCs from hematopoietic precursor cells with GM-CSF and G-CSF in vitro We found that the generation of suppressive IMCs was accompanied by increased glycolysis, but not affected by glucose deprivation due to alternative catabolism. Generation of IMCs relied on glutaminolysis, regardless of glucose availability. Glutamine metabolism not only supported the expansion of IMCs with glutamine-derived α-ketoglutarate but also regulated the suppressive capacity through the glutamate-NMDA receptor axis. Moreover, inhibition of glutaminase GLS1 enhanced the therapeutic efficacy of anti-PD-L1 treatment, with reduced arginase 1+ myeloid cells, increased CD8+, IFNγ+ and granzyme B+ T cells, and delayed tumor growth in an ICB-resistant mouse model. Our work identified a novel regulatory mechanism of glutamine metabolism in controlling the generation of suppressive IMCs in the TME.
Assuntos
Glutamina/metabolismo , Glicólise , Imunossupressores/imunologia , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/metabolismo , Microambiente Tumoral/imunologia , Animais , Apresentação de Antígeno/imunologia , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Glutamina/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Células Mieloides/metabolismo , Neoplasias/patologia , Transdução de Sinais , Linfócitos T/imunologiaRESUMO
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease localized to China, Japan, and Korea that is characterized by severe hemorrhage and a high fatality rate. Currently, no specific vaccine or treatment has been approved for this disease. To develop a therapeutic agent for SFTS, we isolated antibodies from a phage-displayed antibody library that was constructed from a patient who recovered from SFTS virus (SFTSV) infection. One antibody, designated as Ab10, was reactive to the Gn envelope glycoprotein of SFTSV and protected host cells and A129 mice from infection in both in vitro and in vivo experiments. Notably, Ab10 protected 80% of mice, even when injected 5 days after inoculation with a lethal dose of SFTSV. Using cross-linker assisted mass spectrometry and alanine scanning, we located the non-linear epitope of Ab10 on the Gn glycoprotein domain II and an unstructured stem region, suggesting that Ab10 may inhibit a conformational alteration that is critical for cell membrane fusion between the virus and host cell. Ab10 reacted to recombinant Gn glycoprotein in Gangwon/Korea/2012, HB28, and SD4 strains. Additionally, based on its epitope, we predict that Ab10 binds the Gn glycoprotein in 247 of 272 SFTSV isolates previously reported. Together, these data suggest that Ab10 has potential to be developed into a therapeutic agent that could protect against more than 90% of reported SFTSV isolates.
Assuntos
Anticorpos Neutralizantes/metabolismo , Phlebovirus/imunologia , Adulto , Animais , Anticorpos Neutralizantes/fisiologia , Anticorpos Antivirais/metabolismo , Infecções por Bunyaviridae/terapia , Epitopos/imunologia , Feminino , Febre , Glutamina/imunologia , Glutamina/metabolismo , Glicoproteínas/imunologia , Células HEK293 , Humanos , Leucopenia , Masculino , Camundongos , Camundongos Knockout , Testes de Neutralização , Phlebovirus/patogenicidade , República da Coreia , Trombocitopenia/imunologia , Proteínas do Envelope Viral/imunologiaRESUMO
KIR2DL2 and KIR2DL3 segregate as alleles of a single locus in the centromeric motif of the killer cell immunoglobulin-like receptor (KIR) gene family. Although KIR2DL2/L3 polymorphism is known to be associated with many human diseases and is an important factor for donor selection in allogeneic hematopoietic stem cell transplantation, the molecular determinant of functional diversity among various alleles is unclear. In this study we found that KIR2DL2/L3 with glutamic acid at position 35 (E(35)) are functionally stronger than those with glutamine at the same position (Q(35)). Cytotoxicity assay showed that NK cells from HLA-C1 positive donors with KIR2DL2/L3-E(35) could kill more target cells lacking their ligands than NK cells with the weaker -Q(35) alleles, indicating better licensing of KIR2DL2/L3(+) NK cells with the stronger alleles. Molecular modeling analysis reveals that the glutamic acid, which is negatively charged, interacts with positively charged histidine located at position 55, thereby stabilizing KIR2DL2/L3 dimer and reducing entropy loss when KIR2DL2/3 binds to HLA-C ligand. The results of this study will be important for future studies of KIR2DL2/L3-associated diseases as well as for donor selection in allogeneic stem cell transplantation.
Assuntos
Ácido Glutâmico/genética , Glutamina/genética , Antígenos HLA-C/genética , Células Matadoras Naturais/imunologia , Polimorfismo de Nucleotídeo Único , Receptores KIR2DL2/genética , Receptores KIR2DL3/genética , Alelos , Animais , Linhagem Celular , Citotoxicidade Imunológica , Regulação da Expressão Gênica , Genótipo , Ácido Glutâmico/química , Ácido Glutâmico/imunologia , Glutamina/química , Glutamina/imunologia , Antígenos HLA-C/química , Antígenos HLA-C/imunologia , Humanos , Células Matadoras Naturais/citologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Cultura Primária de Células , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína , Receptores KIR2DL2/química , Receptores KIR2DL2/imunologia , Receptores KIR2DL3/química , Receptores KIR2DL3/imunologia , Transdução de SinaisRESUMO
A hallmark of the gluten-driven enteropathy celiac disease is autoantibody production towards the enzyme transglutaminase 2 (TG2) that catalyzes the formation of covalent protein-protein cross-links. Activation of TG2-specific B cells likely involves gluten-specific CD4 T cells as production of the antibodies is dependent on disease-associated HLA-DQ allotypes and dietary intake of gluten. IgA plasma cells producing TG2 antibodies with few mutations are abundant in the celiac gut lesion. These plasma cells and serum antibodies to TG2 drop rapidly after initiation of a gluten-free diet, suggestive of extrafollicular responses or germinal center reactions of short duration. High antigen avidity is known to promote such responses, and is also important for breakage of self-tolerance. We here inquired whether TG2 avidity could be a feature relevant to celiac disease. Using recombinant enzyme we show by dynamic light scattering and gel electrophoresis that TG2 efficiently utilizes itself as a substrate due to conformation-dependent homotypic association, which involves the C-terminal domains of the enzyme. This leads to the formation of covalently linked TG2 multimers. The presence of exogenous substrate such as gluten peptide does not inhibit TG2 self-cross-linking, but rather results in formation of TG2-TG2-gluten complexes. The celiac disease autoantibody epitopes, clustered in the N-terminal part of TG2, are conserved in the TG2-multimers as determined by mass spectrometry and immunoprecipitation analysis. TG2 multimers are superior to TG2 monomer in activating A20 B cells transduced with TG2-specific B-cell receptor, and uptake of TG2-TG2-gluten multimers leads to efficient activation of gluten-specific T cells. Efficient catalytic self-multimerization of TG2 and generation of multivalent TG2 antigen decorated with gluten peptides suggest a mechanism by which self-reactive B cells are activated to give abundant numbers of plasma cells in celiac disease. Importantly, high avidity of the antigen could explain why TG2-specific plasma cells show signs of an extrafollicular generation pathway.
Assuntos
Autoantígenos/imunologia , Proteínas de Ligação ao GTP/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Proteínas Recombinantes/imunologia , Transglutaminases/imunologia , Animais , Autoantígenos/metabolismo , Linfócitos B/imunologia , Linfócitos B/metabolismo , Sítios de Ligação/genética , Sítios de Ligação/imunologia , Catálise , Doença Celíaca/imunologia , Linhagem Celular Tumoral , Eletroforese em Gel de Poliacrilamida , Epitopos de Linfócito T/imunologia , Proteínas de Ligação ao GTP/genética , Proteínas de Ligação ao GTP/metabolismo , Glutamina/genética , Glutamina/imunologia , Glutamina/metabolismo , Glutens/imunologia , Humanos , Lisina/genética , Lisina/imunologia , Lisina/metabolismo , Modelos Moleculares , Mutação , Conformação Proteica , Proteína 2 Glutamina gama-Glutamiltransferase , Multimerização Proteica , Receptores de Antígenos de Linfócitos B/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Células Sf9 , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transglutaminases/genética , Transglutaminases/metabolismoRESUMO
As part of the innate immune response, neutrophils are at the forefront of defence against infection, resolution of inflammation and wound healing. They are the most abundant leucocytes in the peripheral blood, have a short lifespan and an estimated turnover of 10(10) to 10(11) cells per day. Neutrophils efficiently clear microbial infections by phagocytosis and by oxygen-dependent and oxygen-independent mechanisms. In 2004, a new neutrophil anti-microbial mechanism was described, the release of neutrophil extracellular traps (NETs) composed of DNA, histones and anti-microbial peptides. Several microorganisms, bacterial products, as well as pharmacological stimuli such as PMA, were shown to induce NETs. Neutrophils contain relatively few mitochondria, and derive most of their energy from glycolysis. In this scenario we aimed to analyse some of the metabolic requirements for NET formation. Here it is shown that NETs formation is strictly dependent on glucose and to a lesser extent on glutamine, that Glut-1, glucose uptake, and glycolysis rate increase upon PMA stimulation, and that NET formation is inhibited by the glycolysis inhibitor, 2-deoxy-glucose, and to a lesser extent by the ATP synthase inhibitor oligomycin. Moreover, when neutrophils were exposed to PMA in glucose-free medium for 3 hr, they lost their characteristic polymorphic nuclei but did not release NETs. However, if glucose (but not pyruvate) was added at this time, NET release took place within minutes, suggesting that NET formation could be metabolically divided into two phases; the first, independent from exogenous glucose (chromatin decondensation) and, the second (NET release), strictly dependent on exogenous glucose and glycolysis.
Assuntos
Armadilhas Extracelulares/metabolismo , Glucose/metabolismo , Neutrófilos/metabolismo , Carcinógenos/farmacologia , Desoxiglucose/farmacologia , Inibidores Enzimáticos/farmacologia , Armadilhas Extracelulares/imunologia , Glucose/imunologia , Transportador de Glucose Tipo 1/imunologia , Transportador de Glucose Tipo 1/metabolismo , Glutamina/imunologia , Glutamina/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Neutrófilos/imunologia , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
Post-translational modification of proteins by deamidation or transamidation by tissue transglutaminase (tTG) has been suggested as a possible mechanism for the development of autoimmunity. Sequence analysis of protein kinase C delta (PKCδ) identified an amino acid motif that suggested the possibility that PKCδ was a glutamine substrate of tTG and MALDI-TOF analysis of synthesised peptides from PKCδ proved that this was the case. Polymerisation experiments using recombinant tTG and biotinylated hexapeptide substrate incorporation assays demonstrated that PKCδ is a substrate for tTG-mediated transamidation. Elevated levels of anti-PKCδ antibodies were detected in sera from patients with coeliac disease (p<0.0001) but not from patients with other autoimmune disorders. These data suggest that a subset of patients with coeliac disease produce autoantibodies against PKCδ and that this response may stem from a tTG-PKCδ substrate interaction.
Assuntos
Autoantígenos/imunologia , Doença Celíaca/imunologia , Proteínas de Ligação ao GTP/imunologia , Proteína Quinase C-delta/imunologia , Transglutaminases/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/sangue , Autoantígenos/metabolismo , Western Blotting , Doença Celíaca/metabolismo , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Proteínas de Ligação ao GTP/metabolismo , Glutamina/genética , Glutamina/imunologia , Glutamina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Ligação Proteica , Proteína 2 Glutamina gama-Glutamiltransferase , Proteína Quinase C-delta/genética , Proteína Quinase C-delta/metabolismo , Processamento de Proteína Pós-Traducional/imunologia , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Proteínas Recombinantes/metabolismo , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Especificidade por Substrato , Transglutaminases/metabolismo , Adulto JovemRESUMO
PURPOSE OF REVIEW: Glutamine is largely synthesized in skeletal muscles and provides fuel to rapidly dividing cells of the immune system and precursors to gluconeogenesis in the liver. Physical exercise is known to affect glutamine synthesis and to modulate glutamine uptake. Overtraining is frequently associated with reduced availability of glutamine and decreased immunocompetence. Inactivity affects glutamine metabolism, but this subject was poorly investigated. RECENT FINDINGS: Strenuous physical exercise as well as exhaustive training programs lead to glutamine depletion due to lowered synthesis and enhanced uptake by liver and immune cells. Evidence suggests that postexercise glutamine depletion is associated with immunodepression. Counterwise, moderate training leads to improved glutamine availability due to a positive balance between muscle synthesis and peripheral clearance. Physical inactivity, as investigated by experimental bed rest in healthy volunteers, reduced glutamine synthesis and availability. SUMMARY: After exercise, a reduced glutamine availability may be considered as a marker of overtraining. An increased glutamine availability may contribute to decreased inflammation and health benefits associated with optimal training. Thus, glutamine supplementation may enhance immunocompetence after strenuous exercise. The potential of glutamine supplementation during physical inactivity needs to be explored.
Assuntos
Exercício Físico/fisiologia , Glutamina/metabolismo , Repouso em Cama , Suplementos Nutricionais , Glutamina/imunologia , Humanos , Sistema Imunitário/metabolismo , Inflamação/prevenção & controle , Fígado/metabolismo , Músculo Esquelético/metabolismo , Valores de ReferênciaRESUMO
Glutamine is the most abundant free amino acid of the human body. Besides its role as a constituent of proteins and its importance in amino acid transamination, glutamine has regulatory capacity in immune and cell modulation. Glutamine deprivation reduces proliferation of lymphocytes, influences expression of surface activation markers on lymphocytes and monocytes, affects the production of cytokines, and stimulates apoptosis. Moreover, glutamine administration seems to have a positive effect on glucose metabolism in the state of insulin resistance. Glutamine influences a variety of different molecular pathways. Glutamine stimulates the formation of heat shock protein 70 in monocytes by enhancing the stability of mRNA, influences the redox potential of the cell by enhancing the formation of glutathione, induces cellular anabolic effects by increasing the cell volume, activates mitogen-activated protein kinases, and interacts with particular aminoacyl-transfer RNA synthetases in specific glutamine-sensing metabolism. Glutamine is applied under clinical conditions as an oral, parenteral, or enteral supplement either as the single amino acid or in the form of glutamine-containing dipeptides for preventing mucositis/stomatitis and for preventing glutamine-deficiency in critically ill patients. Because of the high turnover rate of glutamine, even high amounts of glutamine up to a daily administration of 30 g can be given without any important side effects.
Assuntos
Glutamina/fisiologia , Necessidades Nutricionais , Transdução de Sinais/fisiologia , Aminoácidos/fisiologia , Apoptose/fisiologia , Tamanho Celular , Glutamina/imunologia , Glutationa/metabolismo , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/fisiologia , Homeostase , Humanos , Linfócitos/imunologia , Monócitos/fisiologiaRESUMO
This research investigated the effect of glutamine (Gln) depletion on leucocyte-dependent inflammatory events. Rats were treated intraperitoneally, 16 hr prior to the peak of every parameter evaluated, with either 0.9% NaCl, methionine-sulphoximine (MSO, an inhibitor of endogenous Gln synthesis, 25 mg/kg) or with MSO + Gln (MSO as above plus Gln 3 g/kg in three doses). MSO-induced Gln depletion increased paw oedema induced both by carrageenan (Cg) and by Clostridium difficile toxin A (TxA) (66.2% and 45.5%, respectively; P < 0.05). In dextran-injected animals, oedema and myeloperoxidase (MPO) activity were not modified by Gln depletion. In Cg-treated paws, Gln depletion increased MPO activity by 44% (P < 0.05), interleukin-1beta (IL-1beta) and tumour necrosis factor-alpha (TNF-alpha) concentrations by 47% and 52%, respectively (P < 0.05), and immunostaining for TNF-alpha in paw tissue. In TxA-injected paws, Gln depletion increased MPO activity (46%; P < 0.05). Gln depletion increased Cg- and TxA-induced neutrophil migration to subcutaneous air pouches by 56% and 77% (P < 0.05), respectively, but did not affect migration induced by N-formyl-methionyl-leucyl-phenylalanine (fMLP). Gln infusions reversed all the effects of MSO. Leucocyte counts did not differ between groups. Gln depletion potentiates acute inflammation, possibly by increasing neutrophil migration through resident cell activation and production of IL-1beta and TNF-alpha. Gln supplementation reverses these effects and may be useful during inflammatory catabolic stress.
Assuntos
Glutamina/imunologia , Inflamação/imunologia , Infiltração de Neutrófilos/imunologia , Animais , Toxinas Bacterianas , Carragenina , Edema/induzido quimicamente , Edema/imunologia , Enterotoxinas , Feminino , Glutamina/sangue , Glutamina/deficiência , Inflamação/induzido quimicamente , Interleucina-1/biossíntese , Contagem de Leucócitos , Masculino , Peroxidase/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/biossínteseRESUMO
PURPOSE OF REVIEW: The aim of this review is to describe the clinical relevance of supplementation of glutamine from the recent literature. First, new basic research is examined and subsequently recent clinical trials and a metaanalysis are illustrated. RECENT FINDINGS: Glutamine has a major impact on the functionality of the immune system. It has recently been established that glutamine not only has a protective effect on cells of the immune system, but also on other cells of the body, for instance cardiomyocytes. Evidence is accumulating for an effect of glutamine via glutathione, heat shock proteins as well as taurine. Another area of interest is the way glutamine enhances gut barrier function. More and more research is concentrating on the positive effect of glutamine on the gut-associated lymphoid tissue. SUMMARY: Based on a recent meta-analysis and up-to-date clinical trials, we may conclude that glutamine has a beneficial effect on infectious complications and reduces hospital stay. In critically ill patients glutamine supplementation may reduce morbidity and mortality. The greatest effect was observed in patients receiving high dose parenteral glutamine. A recent study with high dose enteral glutamine demonstrated a reduced mortality in the glutamine supplemented group. In the future more trials with larger numbers of participants are needed, especially with high dose enteral glutamine in the perioperatively and the intensive care unit setting.
Assuntos
Glutamina/uso terapêutico , Animais , Ensaios Clínicos como Assunto/estatística & dados numéricos , Suplementos Nutricionais , Glutamina/imunologia , Glutationa/biossíntese , Glutationa/efeitos dos fármacos , Humanos , Mucosa Intestinal/metabolismo , Intestinos/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Metanálise como Assunto , Isquemia Miocárdica/tratamento farmacológico , Distúrbios Nutricionais/tratamento farmacológico , Apoio Nutricional , Ratos , Traumatismo por Reperfusão/prevenção & controle , Taurina/biossíntese , Taurina/efeitos dos fármacosRESUMO
BACKGROUND & AIMS: A growing number of randomized clinical trials suggest that glutamine (Gln) supplementation may be beneficial in a selected group of patients and conditions. However, the effects of Gln-enriched total parenteral nutrition (TPN) on recovery from acute intra-abdominal infection have not been thoroughly investigated. Therefore, the aim of this study was to investigate whether the provision of Gln-enriched TPN after surgical and medical treatment of secondary peritonitis improves infectious morbidity. METHODS: Thirty-three patients with secondary peritonitis were randomly assigned to receive either standard (n=16) TPN or L-alanyl-L-glutamine-supplemented (n=17) TPN, after medical and surgical treatment of the infectious focus. The two TPN formulae were isonitrogenous and isocaloric, which commenced the morning after surgery and ran continuously for 10 consecutive days. The control group received standard TPN, while the treatment group was given L-alanyl-L-glutamine, 0.40 g/kg/d (Dipeptiven, Fresenius Kabi, Bad Homburg, Germany). Infectious morbidity, nitrogen balance, leukocytes, lymphocytes, subpopulations CD(4) and CD(8), Immunoglobulin A (IgA), total proteins, albumin, hospital and intensive care unit (ICU) stays, and mortality were evaluated. Statistical analysis included one-way ANOVA, the unpaired Student's t-test, the Mann-Whitney U-test, chi(2) test, or Fisher's exact test. RESULTS: Patients in both groups were comparable prior to the operation. Nitrogen balance and the levels of albumin and IgA were significantly better than those in the control group. Also, a significant reduction in the infectious morbidity was found in the Gln-treated group. Lymphocyte counts as well as subpopulations CD(4) and CD(8), and proteins showed a propensity to improvement and a tendency to reduced rates of mortality were observed when comparing the groups. Hospital and ICU stays were similar. CONCLUSION: L-alanyl-L-glutamine-supplemented TPN improved the infectious morbidity of patients with secondary peritonitis. Gln supplementation to parenteral nutrition may be an alternative for enhancing host defenses and improving infectious morbidity.
Assuntos
Alanina/administração & dosagem , Glutamina/administração & dosagem , Nutrição Parenteral Total , Peritonite/mortalidade , Peritonite/terapia , Alanina/imunologia , Análise de Variância , Relação CD4-CD8 , Dipeptídeos/administração & dosagem , Método Duplo-Cego , Feminino , Glutamina/imunologia , Humanos , Imunoglobulina A/sangue , Tempo de Internação , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Nitrogênio/metabolismo , Peritonite/imunologia , Albumina Sérica/análise , Resultado do TratamentoAssuntos
Aminoácidos/imunologia , Proteínas Alimentares/administração & dosagem , Proteínas Alimentares/imunologia , Imunidade/fisiologia , Aminoácidos/uso terapêutico , Formação de Anticorpos/efeitos dos fármacos , Arginina/imunologia , Arginina/uso terapêutico , Cisteína/imunologia , Cisteína/uso terapêutico , Proteínas Alimentares/metabolismo , Proteínas Alimentares/normas , Glutamina/imunologia , Glutamina/uso terapêutico , Humanos , Imunidade/efeitos dos fármacos , Necessidades Nutricionais , Fagocitose/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the effect of carbohydrate supplementation upon some aspects of the immune function in athletes during intense indoor cycling. METHODS: Twelve male athletes cycled for 20 min at a velocity corresponding to 90% of that obtained at the anaerobic threshold and rested for 20 min. This protocol was repeated six times. The athletes received, during the trial, water ad libitum, or a solution of carbohydrate (95% glucose polymers and 5% fructose) at 10% (w/v), 1 g kg h every 20 min, starting at the 10th minute of the first exercise period, plus extra water ad libitum. RESULTS: Exercise induced a reduction in peripheral blood mononuclear cell proliferation (37%) as well as in the production of cytokines by cultured cells (interleukin-1 (IL-1), interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), by 37%, 35%, 26% and 16%, respectively). All of these changes were prevented by the ingestion of a carbohydrate drink by the athletes, except that in IFN-gamma production, which was equally decreased (17%) after the second trial. The concentration of plasma glutamine, an important fuel for immune cells, was decreased in the placebo group but maintained in the group that received carbohydrate. CONCLUSION: Carbohydrate supplementation affects positively the immune response of cyclists by avoiding or minimizing changes in plasma glutamine concentration.
Assuntos
Formação de Anticorpos/imunologia , Carboidratos da Dieta/administração & dosagem , Carboidratos da Dieta/imunologia , Suplementos Nutricionais , Teste de Esforço , Exercício Físico/fisiologia , Adulto , Análise de Variância , Glicemia/imunologia , Estudos Cross-Over , Citocinas/sangue , Citocinas/imunologia , Glutamina/sangue , Glutamina/imunologia , Humanos , Hidrocortisona/sangue , Hidrocortisona/imunologia , Insulina/sangue , Insulina/imunologia , Ácido Láctico/sangue , Ácido Láctico/imunologia , Masculino , Suor/imunologia , Suor/fisiologia , Redução de Peso/imunologia , Redução de Peso/fisiologiaRESUMO
Nutrition and immunology are interrelated. Several nutrients like arginine, glutamine, omega-3-fatty acids and nucleotides enhance cellular immunity, modulate tumor cell metabolism and improve clinical outcome in stress situations. Glutamine supplementation has been shown to decrease incidence of sepsis and to reduce length of hospital stay in bone marrow transplant patients, low birth weight infants, surgical and multiple trauma patients. Studies with arginine have shown a reduction in infectious complications and lower mortality, however a better understanding of the biology of arginine is needed. Omega-3-fatty acid supplimentation as in fish oil stimulates the immune system. The beneficial effects of immunonutrition in surgical patients has been demonstrated in several studies. It significantly reduces infectious complications and length of hospital stay. In critically ill patients immunonutrition may decrease infectious complications but it is not associated with a mortality advantage. Pediatric experience is limited, but the future is promising.
Assuntos
Aminoácidos/imunologia , Ácidos Graxos Ômega-3/imunologia , Imunidade/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição , Aminoácidos/uso terapêutico , Arginina/imunologia , Ácidos Graxos Ômega-3/uso terapêutico , Glutamina/imunologia , Humanos , Nucleotídeos/imunologia , Taurina/imunologiaRESUMO
BACKGROUND: A significant body of clinical literature demonstrates that enteral feeding significantly reduces the incidence of pneumonia compared to patients fed parenterally. An immunologic link between the gastrointestinal tract and respiratory tract is postulated via the common mucosal immune hypothesis. This hypothesis states that cells are sensitized within the Peyer's patches of the small intestine and are subsequently distributed to submucosal locations in both intestinal and extra intestinal sites. This system is exquisitely sensitive to route and type of nutrition. DATA SOURCE: This review examines the laboratory data regarding cell numbers, cell phenotypes, cytokine profile, and immunologic function in both intestinal and extra intestinal sites in animals that have been administered either parenteral feeding or various types of enteral feeding. It also establishes links between a specific nutrient, glutamine, the enteric nervous system, by way of neuropeptides, and mucosal immunity. CONCLUSION: Progress in understanding relationships between nutrient availability, enteric nervous system stimulation, and nutrient delivery on mucosal immunity offers opportunities to explore immune systems previously not appreciated by clinicians and basic scientists. These opportunities offer new challenges to the physician scientist, basic scientist, and clinician to understand, manipulate, and apply these concepts to the critically ill patient population by favorably influencing immunologic barriers and the inflammatory response.