RESUMEN
The innate immunity protein Tag7 (PGRP-S, PGLYRP1) is involved in antimicrobial and antitumor defense. As shown in our previous studies, Tag7 specifically interacts with the major heat shock protein Hsp70 to form a stable Tag7-Hsp70 complex with cytotoxic activity against tumor cells. A stable complex of Tag7 with the calcium-binding protein Mts1 (S100A4) stimulates migration of lymphocytes. Moreover, Tag7 can activate cytotoxic lymphocytes that recognize and kill HLA-negative tumor cells. Here, we have shown that Tag 7 treatment of human peripheral blood mononuclear cells (PBMCs) results in activation of different cytotoxic lymphocyte populations-natural killer (NK) cells and CD8+ NKG2D+ T lymphocytes-that kill Moloney murine leukemia virus (MMLV) infected SC-1 cells using different mechanisms of cell death induction. This mechanism in NK cells is based on the release of granzymes, which activate apoptosis in target cells, while CD8+ NKG2D+ T lymphocytes recognize the noncanonical MicA antigen on the surface of virus-containing cells and kill them via the FasL-Fas interaction, triggering the apoptotic or necroptotic cell death pathway. Preliminary incubation of PBMCs with virus-infected cells and following incubation with Tag7 results in activation of lymphocytes with a different phenotype. These lymphocytes change the spectrum of target cells and the mechanism of cell death induction, and their interaction with target cells is not species-specific. © 2017 IUBMB Life, 69(12):971-977, 2017.
Asunto(s)
Citocinas/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Proteína Ligando Fas/inmunología , Células Asesinas Naturales/inmunología , Linfocitos T Citotóxicos/inmunología , Receptor fas/inmunología , Animales , Apoptosis/genética , Apoptosis/inmunología , Línea Celular , Técnicas de Cocultivo , Citocinas/genética , Citocinas/farmacología , Proteína Ligando Fas/genética , Fibroblastos/inmunología , Fibroblastos/virología , Expresión Génica , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunidad Innata , Células Asesinas Naturales/citología , Células Asesinas Naturales/efectos de los fármacos , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/efectos de los fármacos , Ratones , Virus de la Leucemia Murina de Moloney/crecimiento & desarrollo , Virus de la Leucemia Murina de Moloney/inmunología , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/inmunología , Necrosis/genética , Necrosis/inmunología , Cultivo Primario de Células , Unión Proteica , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/efectos de los fármacos , Receptor fas/genéticaRESUMEN
A diverse collection of 40 derivatives of benzohydroxamic acid (BHAs) of various structural groups were synthesized and tested against hepatitis C virus (HCV) in full-genome replicon assay. Some of these compounds demonstrated an exceptional activity, suppressing viral replication at sub-micromolar concentrations. The compounds were inactive against key viral enzymes NS3, and NS5B in vitro assays, suggesting host cell inhibition target(s). The testing results were consistent with metal coordination by the BHAs hydroxamic group in complex with a target(s). Remarkably, this class of compounds did not suppress poliomyelitis virus (PV) propagation in RD cells indicating a specific antiviral activity of BHAs against HCV.
Asunto(s)
Antivirales/química , Antivirales/farmacología , Hepacivirus/efectos de los fármacos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Animales , Línea Celular , Genoma Viral/efectos de los fármacos , Hepacivirus/enzimología , Hepacivirus/genética , Hepatitis C/tratamiento farmacológico , Hepatitis C/virología , Humanos , Poliovirus/efectos de los fármacos , Replicón/efectos de los fármacosRESUMEN
All-trans-retinoic acid (atRA), the oxidized form of vitamin A (retinol), regulates a wide variety of biological processes, such as cell proliferation and differentiation. Multiple alcohol, retinol and retinaldehyde dehydrogenases (ADHs, RDHs, RALDHs) as well as aldo-keto reductases (AKRs) catalyze atRA production. The reduced atRA biosynthesis has been observed in several human tumors, including colorectal cancer. However, subsets of atRA-synthesizing enzymes have not been determined in colorectal tumors. We investigated the expression patterns of genes involved in atRA biosynthesis in normal human colorectal tissues, primary carcinomas and cancer cell lines by RT-PCR. These genes were identified using transcriptomic data analysis (expressed sequence tags, RNA-sequencing, microarrays). Our results indicate that each step of the atRA biosynthesis pathway is dysregulated in colorectal cancer. Frequent and significant decreases in the mRNA levels of the ADH1B, ADH1C, RDHL, RDH5 and AKR1B10 genes were observed in a majority of colorectal carcinomas. The expression levels of the RALDH1 gene were reduced, and the expression levels of the cytochrome CYP26A1 gene increased. The human colon cancer cell lines showed a similar pattern of changes in the mRNA levels of these genes. A dramatic reduction in the expression of genes encoding the predominant retinol-oxidizing enzymes could impair atRA production. The most abundant of these genes, ADH1B and ADH1C, display decreased expression during progression from adenoma to early and more advanced stage of colorectal carcinomas. The diminished atRA biosynthesis may lead to alteration of cell growth and differentiation in the colon and rectum, thus contributing to the progression of colorectal cancer.
Asunto(s)
Adenoma/genética , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Bases de Datos Factuales , Perfilación de la Expresión Génica , Tretinoina/metabolismo , 3-Hidroxiesteroide Deshidrogenasas/genética , Adenoma/patología , Alcohol Deshidrogenasa/genética , Oxidorreductasas de Alcohol/genética , Aldehído Reductasa/genética , Aldo-Ceto Reductasas , Estudios de Casos y Controles , Colon/metabolismo , Neoplasias Colorrectales/patología , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Recto/metabolismoRESUMEN
The influence of beta-endorphin and immunorphin on human leukemic cell growth in vitro was studied. It was shown that both peptides increase the growth of T-lymphoblastoid cells in a dose-dependent manner. The effect of these peptides on the 3H-thymidine incorporation into T-lymphoblastoid cell line Jurkat was not reversed by the antagonist of opioid receptor naloxone. Interestingly, these peptides had no effect on B-lymphoblastoid and promyelocyte cell growth, however they enhance 3H-thymidine incorporation into myeloid cell lines.