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1.
Expert Opin Drug Metab Toxicol ; 16(1): 11-30, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31903790

RESUMO

Introduction: Chemokine receptors are important therapeutic targets for the treatment of many human diseases. This study will provide an overview of approved chemokine receptor antagonists and promising candidates in advanced clinical trials.Areas covered: We will describe clinical aspects of chemokine receptor antagonists regarding their clinical efficacy, mechanisms of action, and re-purposed applications.Expert opinion: Three chemokine antagonists have been approved: (i) plerixafor is a small-molecule CXCR4 antagonist that mobilizes hematopoietic stem cells; (ii) maraviroc is a small-molecule CCR5 antagonist for anti-HIV treatment; and (iii) mogamulizumab is a monoclonal-antibody CCR4 antagonist for the treatment of mycosis fungoides or Sézary syndrome. Moreover, phase 3 trials are ongoing to evaluate many potent candidates, including CCR5 antagonists (e.g. leronlimab), dual CCR2/CCR5 antagonists (e.g. cenicriviroc), and CXCR4 antagonists (e.g. balixafortide, mavorixafor, motixafortide). The success of chemokine receptor antagonists depends on the selective blockage of disease-relevant chemokine receptors which are indispensable for disease progression. Although clinical translation has been slow, antagonists targeting chemokine receptors with multifaced functions offer the potential to treat a broad spectrum of human diseases.


Assuntos
Desenvolvimento de Medicamentos , Receptores de Quimiocinas/antagonistas & inibidores , Animais , Humanos , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Receptores CCR4/antagonistas & inibidores , Receptores CCR4/metabolismo , Receptores CCR5/efeitos dos fármacos , Receptores CCR5/metabolismo , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/metabolismo , Receptores de Quimiocinas/metabolismo
2.
Rinsho Ketsueki ; 60(8): 968-972, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31484897

RESUMO

Adult T-cell leukemia-lymphoma (ATL) is a peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Patients with aggressive ATL exhibit poor outcomes, even with dose-dense intensive chemotherapy. Thus, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered in all patients eligible for transplant. However, patients with aggressive ATL often have chemo-refractoriness or experience early relapse during chemotherapy. Allo-HSCT is often ineffective in patients with active disease status. Mogamulizumab (Moga) was approved in 2012 in Japan as a potent treatment option for patients with relapsed or refractory ATL. However, there is a major concern that the use of Moga before allo-HSCT could increase the risk of post-transplant complications, such as graft-versus-host disease (GVHD), because Moga depletes regulatory T cells. Here, we would like to describe the possible effects of pre-transplant Moga on post-transplant complications, such as acute GVHD, and to discuss how Moga could be efficiently incorporated in the treatment regimen of patients with aggressive ATL to maximize the expected clinical benefit.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Vírus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T do Adulto , Adulto , Humanos , Japão , Receptores CCR4 , Transplante Homólogo
3.
Nucleic Acids Res ; 47(17): 9282-9295, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31340047

RESUMO

XRN1 is the major cytoplasmic exoribonuclease in eukaryotes, which degrades deadenylated and decapped mRNAs in the last step of the 5'-3' mRNA decay pathway. Metazoan XRN1 interacts with decapping factors coupling the final stages of decay. Here, we reveal a direct interaction between XRN1 and the CCR4-NOT deadenylase complex mediated by a low-complexity region in XRN1, which we term the 'C-terminal interacting region' or CIR. The CIR represses reporter mRNA deadenylation in human cells when overexpressed and inhibits CCR4-NOT and isolated CAF1 deadenylase activity in vitro. Through complementation studies in an XRN1-null cell line, we dissect the specific contributions of XRN1 domains and regions toward decay of an mRNA reporter. We observe that XRN1 binding to the decapping activator EDC4 counteracts the dominant negative effect of CIR overexpression on decay. Another decapping activator PatL1 directly interacts with CIR and alleviates the CIR-mediated inhibition of CCR4-NOT activity in vitro. Ribosome profiling revealed that XRN1 loss impacts not only on mRNA levels but also on the translational efficiency of many cellular transcripts likely as a consequence of incomplete decay. Our findings reveal an additional layer of direct interactions in a tightly integrated network of factors mediating deadenylation, decapping and 5'-3' exonucleolytic decay.


Assuntos
Proteínas de Ligação a DNA/genética , Exorribonucleases/genética , Proteínas Associadas aos Microtúbulos/genética , Capuzes de RNA/genética , Estabilidade de RNA/genética , Endorribonucleases/genética , Humanos , Complexos Multiproteicos/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Proteínas/genética , RNA Mensageiro/química , RNA Mensageiro/genética , Receptores CCR4/genética , Proteínas Repressoras/genética , Transativadores/genética , Fatores de Transcrição/genética
4.
Nat Commun ; 10(1): 3173, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320642

RESUMO

CCR4-NOT is a conserved multiprotein complex which regulates eukaryotic gene expression principally via shortening of poly(A) tails of messenger RNA or deadenylation. Here, we reconstitute a complete, recombinant human CCR4-NOT complex. Our reconstitution strategy permits strict compositional control to test mechanistic hypotheses with purified component variants. CCR4-NOT is more active and selective for poly(A) than the isolated exonucleases, CCR4a and CAF1, which have distinct deadenylation profiles in vitro. The exonucleases require at least two out of three conserved non-enzymatic modules (CAF40, NOT10:NOT11 or NOT) for full activity in CCR4-NOT. CAF40 and the NOT10:NOT11 module both bind RNA directly and stimulate deadenylation in a partially redundant manner. Linear motifs from different RNA-binding factors that recruit CCR4-NOT to specific mRNAs via protein-protein interactions with CAF40 can inhibit bulk deadenylation. We reveal an additional layer of regulatory complexity to the human deadenylation machinery, which may prime it either for general or target-specific degradation.


Assuntos
Exorribonucleases/metabolismo , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Receptores CCR4/genética , Humanos , Complexos Multiproteicos/síntese química , Complexos Multiproteicos/genética , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Poli A/metabolismo , RNA Mensageiro/genética , Receptores CCR4/metabolismo , Proteínas Recombinantes/genética , Ribonucleases/metabolismo , Fatores de Transcrição/metabolismo
5.
Fish Shellfish Immunol ; 93: 50-54, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31276790

RESUMO

Atypical chemokine receptor 4 (ACKR4) is regulated by cytokines, binds chemokines and regulates the chemokine gradient. We verified the cDNA sequence by confirming ACKR4 from red sea bream (PmACKR4) by next generation sequencing (NGS) and analysed the molecular characteristics and gene expression profile. In the analysis using the predicted amino acid sequence of PmACKR4, a highly conserved G protein-coupled receptor 1 region and two cysteine residues were identified and included in the ACKR4 teleost cluster in the phylogenetic analysis. In healthy red sea bream, PmACKR4 mRNA was expressed at the highest levels in head kidney and was upregulated in all immune -related tissues used in the experiment after challenges with Streptococcus iniae (S. iniae) and red sea bream iridovirus (RSIV). These results suggest that ACKR4 is highly conserved in red sea bream and may play an important role in the immune system as previously reported. It is thought that ACKR4 acts as a regulator of immune -related cells via immune reactions after pathogenic infection.


Assuntos
Doenças dos Peixes/imunologia , Regulação da Expressão Gênica/imunologia , Imunidade Inata/genética , Receptores CCR4/genética , Dourada/imunologia , Sequência de Aminoácidos , Animais , Infecções por Vírus de DNA/imunologia , Infecções por Vírus de DNA/veterinária , Perfilação da Expressão Gênica/veterinária , Iridoviridae/fisiologia , Filogenia , Receptores CCR4/metabolismo , Infecções Estreptocócicas/imunologia , Infecções Estreptocócicas/veterinária , Streptococcus iniae/fisiologia
6.
Cancer Sci ; 110(9): 2783-2793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325403

RESUMO

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CCL22/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Quimiocina CCL22/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Acta Derm Venereol ; 99(9): 809-812, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31045236

RESUMO

Tumor cells in cutaneous T-cell lymphoma express limited numbers of chemokine receptors. We investigated the expression patterns of CXCR3, CCR3, CCR4 and CCR10 in mycosis fungoides, Sézary syndrome, lym-phomatoid papulosis and anaplastic large cell lymphoma in 121 skin biopsy samples. CXCR3 was expressed in 86% of mycosis fungoides cases but in no anaplastic large cell lymphoma cases. CCR3 was expressed in 73% of cases of CD30+ lymphoproliferative disorders such as lymphomatoid papulosis and anaplastic large cell lymphoma. Mycosis fungoides/Sézary syndrome patients with high CCR3 or CCR4 expression had a poorer survival prognosis than mycosis fungoides/Sézary syndrome patients whose tumor cells did not express these receptors. CCR10 was expressed in 50% of mycosis fungoides/Sézary syndrome cases and in 13% of cases with CD30+ lym-phoproliferative disorders. These results suggest that differential patterns of CXCR3, CCR3, CCR4 and CCR10 expression are useful for the diagnosis of cutaneous T-cell lymphoma. Moreover, expression of CCR3 or CCR4 suggests a poor prognosis in mycosis fungoides/Sézary syndrome.


Assuntos
Biomarcadores Tumorais/análise , Micose Fungoide/imunologia , Receptores CCR3/análise , Receptores CCR4/análise , Síndrome de Sézary/imunologia , Neoplasias Cutâneas/imunologia , Humanos , Micose Fungoide/mortalidade , Micose Fungoide/patologia , Prognóstico , Receptores CCR10/análise , Receptores CXCR3/análise , Síndrome de Sézary/mortalidade , Síndrome de Sézary/patologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Regulação para Cima
8.
Plant Cell Physiol ; 60(9): 2015-2025, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31093672

RESUMO

CCR4/CAF1 are widely conserved deadenylases in eukaryotes. They form a large complex that includes NOT1 as a scaffold protein and various NOT proteins that are core components of multiple levels of gene expression control. The CCR4-NOT complex also contains several RNA-binding proteins as accessory proteins, which are required for target recognition by CCR4/CAF1 deadenylases. AtCCR4a/b, orthologs of human CCR4 in Arabidopsis, have various physiological effects. AtCCR4 isoforms are likely to have specific target mRNAs related to each physiological effect; however, AtCCR4 does not have RNA-binding capability. Therefore, identifying factors that interact with AtCCR4a/b is indispensable to understand its function as a regulator of gene expression, as well as the target mRNA recognition mechanism. Here, we identified putative components of the AtCCR4-NOT complex using co-immunoprecipitation in combination with mass spectrometry using FLAG-tagged AtCCR4b and subsequent verification with a yeast two-hybrid assay. Interestingly, four of 11 AtCAF1 isoforms interacted with both AtCCR4b and AtNOT1, whereas two isoforms interacted only with AtNOT1 in yeast two-hybrid assays. These results imply that Arabidopsis has multiple CCR4-NOT complexes with various combinations of deadenylases. We also revealed that the RNA-binding protein Arabidopsis Pumilio 5 and 2 interacted with AtCCR4a/b in the cytoplasm with a few foci.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas Repressoras/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Citoplasma/metabolismo , Filogenia , Isoformas de Proteínas , Proteínas de Ligação a RNA/genética , Receptores CCR4/genética , Proteínas Repressoras/genética , Técnicas do Sistema de Duplo-Híbrido
9.
Med. oral patol. oral cir. bucal (Internet) ; 24(3): e354-e363, mayo 2019. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-185644

RESUMO

Background: Diverse studies have evidenced that chemokines can play a critical role in pathogenesis of oral squamous cell carcinoma (SCC). The main chemokines involved in oral carcinogenesis, tumor invasion and metastasis are CCR4, CCR5, CCR7 and CXCR4, and our aim was to evaluate the prognostic value of the immunoexpression of these chemokines in SCC of tongue and floor of the mouth. Material and Methods: A retrospective descriptive study of the immunohistochemical expression of CCR4, CCR5, CCR7 and CXCR4 in paraffin-embedded samples of 124 patients with SCC of the tongue and floor of the mouth was performed, considering 98 cases from Brazil and 26 cases from Chile. Associations between variables were analyzed using chi-square test. Survival curves were performed using the Kaplan-Meier method and compared with long-rank test. For multivariate survival analysis, the Cox hazard model was established. The level of significance established was p ≤ 0.05. Results: The statistical analysis showed that samples with well or moderate WHO model differentiation (p = 0.001) and a high expression of CCR5 (p = 0.05) were significantly associated with a higher disease specific survival, which were also observed in Cox ́s multivariate analysis (p = 0.01). A higher expression of CCR7 (p = 0.01) interfered significantly in disease-free survival in univariate analysis and in Cox ́s multivariate analysis (p = 0.05). Conclusions: These results support additional evidence, showing that chemokine receptors CCR5 and CCR7 are helpful as biomarkers of poor prognosis in patients with SCC of the tongue and floor of the mouth


No disponible


Assuntos
Humanos , Carcinoma de Células Escamosas , Neoplasias da Língua , Neoplasias Bucais , Brasil , Chile , Prognóstico , Receptores CCR4 , Receptores CCR5 , Receptores CCR7 , Receptores CXCR4 , Estudos Retrospectivos
10.
Med Oral Patol Oral Cir Bucal ; 24(3): e354-e363, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31011147

RESUMO

BACKGROUND: Diverse studies have evidenced that chemokines can play a critical role in pathogenesis of oral squamous cell carcinoma (SCC). The main chemokines involved in oral carcinogenesis, tumor invasion and metastasis are CCR4, CCR5, CCR7 and CXCR4, and our aim was to evaluate the prognostic value of the immunoexpression of these chemokines in SCC of tongue and floor of the mouth. MATERIAL AND METHODS: A retrospective descriptive study of the immunohistochemical expression of CCR4, CCR5, CCR7 and CXCR4 in paraffin-embedded samples of 124 patients with SCC of the tongue and floor of the mouth was performed, considering 98 cases from Brazil and 26 cases from Chile. Associations between variables were analyzed using chi-square test. Survival curves were performed using the Kaplan-Meier method and compared with long-rank test. For multivariate survival analysis, the Cox hazard model was established. The level of significance established was p≤0.05. RESULTS: The statistical analysis showed that samples with well or moderate WHO model differentiation (p=0.001) and a high expression of CCR5 (p=0.05) were significantly associated with a higher disease specific survival, which were also observed in Cox's multivariate analysis (p=0.01). A higher expression of CCR7 (p=0.01) interfered significantly in disease-free survival in univariate analysis and in Cox's multivariate analysis (p=0.05). CONCLUSIONS: These results support additional evidence, showing that chemokine receptors CCR5 and CCR7 are helpful as biomarkers of poor prognosis in patients with SCC of the tongue and floor of the mouth.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Bucais , Neoplasias da Língua , Brasil , Chile , Humanos , Prognóstico , Receptores CCR4 , Receptores CCR5 , Receptores CCR7 , Receptores CXCR4 , Estudos Retrospectivos
11.
Nagoya J Med Sci ; 81(1): 1-18, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30962651

RESUMO

CD4+ regulatory T cells (Tregs) expressing the transcription factor forkhead box P3 (FoxP3) play an important role in self-tolerance and immune homeostasis. Tregs have evolved to protect the host from aberrant immune responses against self-components and collateral damages occurring in the process of defense against invading pathogens by softening immune responses. However, they turned to be a scourge in malignant tumors by not only allowing and promoting tumor growth but also suppressing effective antitumor actions, both inherent (host's immune surveillance) and extrinsic (anticancer therapy). An increase in the number of Tregs infiltrating into tumor sites and a concomitant decrease in the number of CD8+ cytotoxic T lymphocytes are associated with a poor prognosis for various types of cancers, marking Tregs as notorious meddlers with an effective antitumor response. Various cancer immunotherapy approaches are often dampened by meddling Tregs, making them one of the major targets in the treatment of cancer. The recent success of immune checkpoint inhibitors (ICIs) that target immune checkpoint molecules expressed by Tregs or effector T cells implies, that "meddling with meddlers" represents an effective strategy in cancer immunotherapy. However, clinical responses to ICIs are effective and durable only in some patients with cancer, whereas more than half of them do not show significant clinical improvement. This implies that a therapeutic approach based on the use of a single ICI, or targeting Tregs alone, is insufficient, highlighting the need for combinatorial approaches. With regard to antitumor immune stimulation, several approaches, such as vaccination with peptides (or the corresponding DNA) to stimulate antigen-presenting CD8+ T cells with tumor-specific neoantigens, cancer/testis antigens, or cancer stem cell antigens, that eventually boost effective cytotoxic antitumor responses are being tested. This review describes the immunosuppressive physiology of Tregs and their meddling with the host's antitumor immunity; current and prospective approaches to curb Tregs; and approaches to augment antitumor immunity.


Assuntos
Linfócitos T Reguladores/metabolismo , Animais , Antígenos de Neoplasias/imunologia , Antígenos de Neoplasias/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Tolerância Imunológica/imunologia , Tolerância Imunológica/fisiologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Modelos Biológicos , Receptor A2A de Adenosina/metabolismo , Receptores CCR4/metabolismo , Receptores de Interleucina-2/metabolismo , Linfócitos T Reguladores/imunologia
12.
Cell Mol Neurobiol ; 39(5): 651-669, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30982091

RESUMO

CKLF1 is a chemokine with increased expression in ischemic brain, and targeting CKLF1 has shown therapeutic effects in cerebral ischemia model. Microglia/macrophage polarization is a mechanism involved in poststroke injury expansion. Considering the quick and obvious response of CKLF1 and expeditious evolution of stroke lesions, we focused on the effects of CKLF1 on microglial/macrophage polarization at early stage of ischemic stroke (IS). The present study is to investigate the CKLF1-mediated expression of microglia/macrophage phenotypes in vitro and in vivo, discussing the involved pathway. Primary microglia culture was used in vitro, and mice transient middle cerebral artery occlusion (MCAO) model was adopted to mimic IS. CKLF1 was added to the primary microglia for 24 h, and we found that CKLF1 modulated primary microglia skew toward M1 phenotype. In mice transient IS model, CKLF1 was stereotactically microinjected to the lateral ventricle of ischemic hemisphere. CKLF1 aggravated ischemic injury, accompanied by promoting microglia/macrophage toward M1 phenotypic polarization. Increased expression of pro-inflammatory cytokines and decreased expression of anti-inflammatory cytokines were observed in mice subjected to cerebral ischemia and administrated with CKLF1. CKLF1-/- mice were used to confirm the effects of CKLF1. CKLF1-/- mice showed lighter cerebral damage and decreased M1 phenotype of microglia/macrophage compared with the WT control subjected to cerebral ischemia. Moreover, NF-κB activation enhancement was detected in CKLF1 treatment group. Our results demonstrated that CKLF1 is an important mediator that skewing microglia/macrophage toward M1 phenotype at early stage of cerebral ischemic injury, which further deteriorates followed inflammatory response, contributing to early expansion of cerebral ischemia injury. Targeting CKLF1 may be a novel way for IS therapy.


Assuntos
Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Polaridade Celular , Quimiocinas/metabolismo , Macrófagos/patologia , Microglia/patologia , Receptores CCR4/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Modelos Animais de Doenças , Infarto da Artéria Cerebral Média/patologia , Inflamação/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Fenótipo
13.
Cancer Invest ; 37(3): 163-173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30907146

RESUMO

To clarify the prognostic impact of tumor-infiltrating effector regulatory T cells (eTregs) in non-small cell lung cancer (NSCLC), eTregs were evaluated by immunohistochemical detection of CCR4 and Foxp3 in 108 consecutive surgical NSCLC tumors. Multivariate analysis showed that a high ratio of CCR4+ eTregs to total Tregs (≥40%) was the only independent risk factor for relapse-free survival (odds ratio [OR]: 6.54, 95% confidence interval: 1.67-25.7, p = .007) and overall survival (OR: 3.76, p = .037) in lung squamous cell carcinoma (SqCC). These results highlight the prognostic importance of the balance of tumor-infiltrating Tregs in resected lung SqCC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Pulmonares/metabolismo , Linfócitos do Interstício Tumoral/metabolismo , Receptores CCR4/biossíntese , Linfócitos T Reguladores/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma de Células Escamosas/diagnóstico , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Prognóstico
14.
Nat Immunol ; 20(4): 493-502, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833792

RESUMO

Interferon-stimulated genes (ISGs) form the backbone of the innate immune system and are important for limiting intra- and intercellular viral replication and spread. We conducted a mass-spectrometry-based survey to understand the fundamental organization of the innate immune system and to explore the molecular functions of individual ISGs. We identified interactions between 104 ISGs and 1,401 cellular binding partners engaging in 2,734 high-confidence interactions. 90% of these interactions are unreported so far, and our survey therefore illuminates a far wider activity spectrum of ISGs than is currently known. Integration of the resulting ISG-interaction network with published datasets and functional studies allowed us to identify regulators of immunity and processes related to the immune system. Given the extraordinary robustness of the innate immune system, this ISG network may serve as a blueprint for therapeutic targeting of cellular systems to efficiently fight viral infections.


Assuntos
Imunidade Inata , Interferons/fisiologia , Mapeamento de Interação de Proteínas , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte/metabolismo , Linhagem Celular , Expressão Gênica , Glicoproteínas/metabolismo , Células HEK293 , Células HeLa , Humanos , Imunidade Inata/genética , Espectrometria de Massas , Receptores CCR4/metabolismo , Receptores de Peptídeos/metabolismo , Ribonucleoproteínas/metabolismo , Proteínas Virais/metabolismo
15.
PLoS Pathog ; 15(1): e1007164, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30703164

RESUMO

With relatively few known specific transcription factors to control the abundance of specific mRNAs, Plasmodium parasites may rely more on the regulation of transcript stability and turnover to provide sufficient gene regulation. Plasmodium transmission stages impose translational repression on specific transcripts in part to accomplish this. However, few proteins are known to participate in this process, and those that are characterized primarily affect female gametocytes. We have identified and characterized Plasmodium yoelii (Py) CCR4-1, a putative deadenylase, which plays a role in the development and activation of male gametocytes, regulates the abundance of specific mRNAs in gametocytes, and ultimately increases the efficiency of host-to-vector transmission. We find that when pyccr4-1 is deleted or its protein made catalytically inactive, there is a loss in the initial coordination of male gametocyte maturation and a reduction of parasite infectivity of the mosquito. Expression of only the N-terminal CAF1 domain of the essential CAF1 deadenylase leads to a similar phenotype. Comparative RNA-seq revealed that PyCCR4-1 affects transcripts important for transmission-related functions that are associated with male or female gametocytes, some of which directly associate with the immunoprecipitated complex. Finally, circular RT-PCR of one of the bound, dysregulated transcripts showed that deletion of the pyccr4-1 gene does not result in gross changes to its UTR or poly(A) tail length. We conclude that the two putative deadenylases of the CAF1/CCR4/NOT complex play critical and intertwined roles in gametocyte maturation and transmission.


Assuntos
Plasmodium falciparum/genética , Receptores CCR4/metabolismo , Animais , Culicidae/metabolismo , Gametogênese/fisiologia , Regulação da Expressão Gênica , Proteínas de Homeodomínio , Masculino , Camundongos , Mosquitos Vetores , Plasmodium/genética , Plasmodium falciparum/metabolismo , Proteínas , RNA Mensageiro/genética , Ribonucleases , Fatores de Transcrição/metabolismo , Ativação Transcricional
16.
Int Immunopharmacol ; 70: 69-79, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30785093

RESUMO

BACKGROUND: IMM-H004 is a novel compound that has been shown to protect against cerebral ischemia/reperfusion injury in our previous works. Chemokine-like factor 1 (CKLF1) is a chemokine that exhibits increased expression in the ischemic brain. Dysregulation of microglia polarization dynamics is a mechanism of injury expansion poststroke. PURPOSES: The aim of present study was to investigate the effects of IMM-H004 on cell viability and microglia phenotypes in BV2 microglia suffering from oxygen-glucose deprivation/reperfusion and discussing the involvement of CKLF1 and possible mechanisms. RESULTS: IMM-H004 protected BV2 microglia from oxygen-glucose deprivation/reperfusion-induced toxicity. We found that the expression of CKLF1 was increased in BV2 microglia with oxygen-glucose deprivation/reperfusion, and IMM-H004 decreased this specially increased expression. Moreover, oxygen-glucose deprivation/reperfusion induced the BV2 microglia to polarize toward an M1 phenotype, and IMM-H004 modulated the polarization shift from the M1 phenotype and skewed toward the M2 phenotype, followed by suppressing the excessive inflammatory response and improving recovery. CKLF1 modulated BV2 microglia toward M1 polarization and induced an inflammatory response. By using receptor inhibitors, we found that OGD/R induced microglia polarization partly through CC chemokine receptor 4. Furthermore, the Co-IP assay showed that IMM-H004 decreased the amount of CKLF1 binding to CC chemokine receptor 4 in the BV2 microglia oxygen-glucose deprivation/reperfusion model. CONCLUSIONS: IMM-H004 protects BV2 microglia against oxygen-glucose deprivation/reperfusion injury partly by modulating microglia polarization and further regulating the inflammatory response. The CKLF1/CCR4 axis may be involved in the protective effects of IMM-H004 modulating microglia polarization.


Assuntos
Quimiocinas/metabolismo , Cumarínicos/farmacologia , Proteínas com Domínio MARVEL/metabolismo , Microglia/patologia , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Diferenciação Celular , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Glucose/metabolismo , Microglia/efeitos dos fármacos , Oxigênio/metabolismo , Ratos , Receptores CCR4/metabolismo , Células Th1/imunologia
17.
Genes Dev ; 33(3-4): 236-252, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30692204

RESUMO

The multisubunit CCR4-NOT mRNA deadenylase complex plays important roles in the posttranscriptional regulation of gene expression. The NOT4 E3 ubiquitin ligase is a stable component of the CCR4-NOT complex in yeast but does not copurify with the human or Drosophila melanogaster complex. Here we show that the C-terminal regions of human and D. melanogaster NOT4 contain a conserved sequence motif that directly binds the CAF40 subunit of the CCR4-NOT complex (CAF40-binding motif [CBM]). In addition, nonconserved sequences flanking the CBM also contact other subunits of the complex. Crystal structures of the CBM-CAF40 complex reveal a mutually exclusive binding surface for NOT4 and Roquin or Bag of marbles mRNA regulatory proteins. Furthermore, CAF40 depletion or structure-guided mutagenesis to disrupt the NOT4-CAF40 interaction impairs the ability of NOT4 to elicit decay of tethered reporter mRNAs in cells. Together with additional sequence analyses, our results reveal the molecular basis for the association of metazoan NOT4 with the CCR4-NOT complex and show that it deviates substantially from yeast. They mark the NOT4 ubiquitin ligase as an ancient but nonconstitutive cofactor of the CCR4-NOT deadenylase with potential recruitment and/or effector functions.


Assuntos
Modelos Moleculares , Domínios e Motivos de Interação entre Proteínas/fisiologia , Receptores CCR4/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Sequência Conservada , Cristalização , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/química , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/genética , Estrutura Quaternária de Proteína , Estabilidade de RNA/genética , Receptores CCR4/química , Fatores de Transcrição/genética
18.
Med Sci Sports Exerc ; 51(2): 379-388, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30649094

RESUMO

Mucosal-associated invariant T (MAIT) cells have properties of both the innate and adaptive immune systems but are an understudied population within exercise immunology. These lymphocytes aggregate at the mucous membranes, but it is unknown if submaximal exercise alters their circulating numbers or function. PURPOSE: To determine the MAIT cell response to submaximal exercise on activation and homing marker expression and stimulated cytokine production. METHODS: Twenty healthy, young, recreationally active males cycled for 40 min at 86% of VT after an overnight fast. Peripheral blood mononuclear cells were isolated and labeled to identify specific MAIT cell populations using flow cytometry. Cytokine production after stimulation was also determined. RESULTS: Mucosal-associated invariant T cells were 2.9% of T cells and increased to 3.9% after exercise and with recovery whereas cell numbers significantly increased by 91.5% after exercise before returning to resting levels. Chemokine and activation marker absolute cell number significantly increased while expression levels remained constant but the high levels of CCR5 may help direct MAIT cells to sites of inflammation. After stimulation, TNFα expression significantly increased after exercise before returning to baseline with a similar trend for IFNγ. CONCLUSIONS: The MAIT cell numbers undergo a partial biphasic response after submaximal exercise and appear to be preferentially mobilized within T cells; however, the magnitude of the submaximal response was attenuated relative to maximal exercise. Stimulated MAIT cells increase TNFα expression, indicating greater responsiveness to pathogens after acute exercise.


Assuntos
Exercício/fisiologia , Células T Invariáveis Associadas à Mucosa/imunologia , Receptores de Retorno de Linfócitos/imunologia , Adolescente , Adulto , Antígenos CD/sangue , Antígenos de Diferenciação de Linfócitos T/sangue , Biomarcadores/sangue , Contagem de Células , Citocinas/sangue , Citocinas/imunologia , Humanos , Lectinas Tipo C/sangue , Leucócitos Mononucleares/imunologia , Ativação Linfocitária , Contagem de Linfócitos , Masculino , Receptores CCR4/sangue , Receptores CCR5/sangue , Receptores CCR6/sangue , Receptores de Retorno de Linfócitos/sangue , Adulto Jovem
19.
Mucosal Immunol ; 12(2): 312-322, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30337650

RESUMO

Malaria-associated acute respiratory distress syndrome (MA-ARDS) and acute lung injury (ALI) are complications that cause lung damage and often leads to death. The MA-ARDS/ALI is associated with a Type 1 inflammatory response mediated by T lymphocytes and IFN-γ. Here, we used the Plasmodium berghei NK65 (PbN)-induced MA-ALI/ARDS model that resembles human disease and confirmed that lung CD4+ and CD8+ T cells predominantly expressed Tbet and IFN-γ. Surprisingly, we found that development of MA-ALI/ARDS was dependent on functional CCR4, known to mediate the recruitment of Th2 lymphocytes and regulatory T cells. However, in this Type 1 inflammation-ARDS model, CCR4 was not involved in the recruitment of T lymphocytes, but was required for the emergence of TNF-α/iNOS producing dendritic cells (Tip-DCs) in the lungs. In contrast, recruitment of Tip-DCs and development of MA-ALI/ARDS were not altered in CCR2-/- mice. Importantly, we showed that NOS2-/- mice are resistant to PbN-induced lung damage, indicating that reactive nitrogen species produced by Tip-DCs play an essential role in inducing MA-ARDS/ALI. Lastly, our experiments suggest that production of IFN-γ primarily by CD8+ T cells is required for inducing Tip-DCs differentiation in the lungs and the development of MA-ALI/ARDS model.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Malária/imunologia , Óxido Nítrico Sintase Tipo II/metabolismo , Plasmodium berghei/fisiologia , Receptores CCR4/metabolismo , Síndrome do Desconforto Respiratório do Adulto/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Receptores CCR4/genética , Fator de Necrose Tumoral alfa/metabolismo
20.
Am J Clin Dermatol ; 20(1): 115-122, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30430444

RESUMO

Cutaneous T-cell lymphomas (CTCLs) are a group of non-Hodgkin's lymphomas that present in the skin. In early-stage disease, the course is generally chronic and indolent; however, in advanced stages of disease, therapies rarely provide long-lasting responses, and the only potential curative therapy is allogeneic hematopoietic stem-cell transplantation. This has led to the search for novel targeted therapies to better treat more advanced stages of CTCLs that cannot be controlled by typical treatment regimens. One area of advancement has been the development of antibodies specifically targeted to cell types that are known to be involved in CTCL. At present, brentuximab vedotin, an antibody-drug conjugate composed of an anti-cluster of differentiation (CD)-30 antibody covalently linked to monomethyl auristatin E, is approved for the treatment of CD30+ lymphoproliferative disorders [lymphomatoid papulosis (LyP) and primary cutaneous-anaplastic large-cell lymphoma (pc-ALCL)] as well as transformed CD30+ mycosis fungoides (MF). Additionally, mogamulizumab, an anti-chemokine receptor 4 (CCR4) monoclonal antibody, is approved for patients with MF or Sézary syndrome (SS) for whom one prior systemic therapy has failed. Trials are underway looking into the use of immune checkpoint inhibitors in the treatment of CTCLs. As we continue to research CTCL, and as antibody-based therapies continue to advance, more antibody-specific targeted therapy could provide alternative treatment regimens for patients with advanced CTCL.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Receptores Coestimuladores e Inibidores de Linfócitos T/antagonistas & inibidores , Imunoterapia/métodos , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/farmacologia , Ensaios Clínicos como Assunto , Receptores Coestimuladores e Inibidores de Linfócitos T/imunologia , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Imunoterapia/tendências , Antígeno Ki-1/antagonistas & inibidores , Antígeno Ki-1/imunologia , Linfoma Cutâneo de Células T/imunologia , Receptores CCR4/antagonistas & inibidores , Receptores CCR4/imunologia , Neoplasias Cutâneas/imunologia , Resultado do Tratamento
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