RESUMEN
Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth-like cells, play an important role in intestinal epithelial homeostasis. IFN-γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN-γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth-like cell secretion. Paneth and Paneth-like secretion downstream of IFN-γ, as identified here, is mTORC1 and necroptosis-dependent. Thus, our findings revealed that the pleiotropic function of IFN-γ also includes the regulation of Paneth cell function in the homeostatic gut.
RESUMEN
The survival of patients with non-Hodgkin's lymphoma (NHL) has substantially improved with current treatments. Nevertheless, the appearance of drug-resistant cancer cells leads to patient relapse. It is therefore necessary to find new antitumor therapies that can completely eradicate transformed cells. Chemotherapy-resistant cancer cells are characterized by the overexpression of members of the anti-apoptotic B-cell lymphoma 2 (Bcl-2) protein family, such as Bcl-XL, Bcl-2, and Mcl-1. We have recently shown that peptides derived from the BH3 domain of the pro-apoptotic Bax protein may antagonize the anti-apoptotic activity of the Bcl-2 family proteins, restore apoptosis, and induce chemosensitization of tumor cells. In this study, we investigated the feasibility of releasing this peptide into the tumor microenvironment using live attenuated Salmonella enterica, which has proven to be an ally in cancer therapy due to its high affinity for tumor tissue, its ability to activate the innate and adaptive antitumor immune responses, and its potential use as a delivery system of heterologous molecules. Thus, we expressed and released the cell-permeable Bax BH3 peptide from the surface of Salmonella enterica serovar Typhimurium SL3261 through the MisL autotransporter system. We demonstrated that this recombinant bacterium significantly decreased the viability and increased the apoptosis of Ramos cells, a human B NHL cell line. Indeed, the intravenous administration of this recombinant Salmonella enterica elicited antitumor activity and extended survival in a xenograft NHL murine model. This antitumor activity was mediated by apoptosis and an inflammatory response. Our approach may represent an eventual alternative to treat relapsing or refractory NHL.
Asunto(s)
Proteínas Bacterianas , Vacunas contra el Cáncer/inmunología , Sistemas de Liberación de Medicamentos , Linfoma no Hodgkin/inmunología , Linfoma no Hodgkin/patología , Proteínas de Transporte de Membrana , Fragmentos de Péptidos/inmunología , Proteínas Proto-Oncogénicas/inmunología , Salmonella enterica/inmunología , Proteína X Asociada a bcl-2/inmunología , Animales , Apoptosis/efectos de los fármacos , Proteínas Bacterianas/química , Vacunas contra el Cáncer/administración & dosificación , Línea Celular , Permeabilidad de la Membrana Celular , Supervivencia Celular , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Humanos , Linfoma no Hodgkin/mortalidad , Linfoma no Hodgkin/terapia , Proteínas de Transporte de Membrana/química , Ratones , Modelos Moleculares , Oligonucleótidos/química , Fragmentos de Péptidos/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Recombinantes , Salmonella enterica/genética , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de Xenoinjerto , Proteína X Asociada a bcl-2/química , Proteína X Asociada a bcl-2/genéticaRESUMEN
BACKGROUND: B cells play an important role in allergic asthma. However, the mechanisms by which these cells are activated in the airways remain poorly understood. METHODS: We used a mouse model of ovalbumin (OVA)-induced allergic inflammation to study CXCL13 and to investigate the concentration of this chemokine in the BAL fluid derived from asthmatic and normal control subjects. RESULTS: We found that OVA-challenged mice upregulate the CXCL13/CXCR5 axis, which is associated with several changes in their airways, including recruitment of B and CD4(+) cells, development of bronchial-associated lymphoid tissue, and airway inflammation. Treating sensitized mice with an anti-CXCL13 antibody reduced cell recruitment, bronchial-associated lymphoid tissue formation, and airways inflammation. Interestingly, measurements of CXCL13 using enzyme-linked immunosorbent assay showed that levels of this cytokine were significantly elevated in BAL fluid from subjects with asthma compared with control subjects (median, 162 [range, 120-296] vs 31 [range, 120-156] pg/mL; P = .005). CONCLUSIONS: All together, these findings suggest that CXCL13 is involved in the allergic airway inflammatory process, and targeting this chemokine may constitute a novel approach in asthma.