RESUMEN
Interleukin-22 (IL-22) is a member of the IL-10 cytokine family that binds to a heterodimeric receptor consisting of IL-22 receptor 1 (IL-22R1) and IL-10R2. IL-22R expression was initially characterized on epithelial cells, and plays an essential role in a number of inflammatory diseases. Recently, a functional receptor was detected on cancer cells such as hepatocarcinoma and lung carcinoma, but its presence was not reported in glioblastoma (GBM). Two GBM cell lines and 10 primary cell lines established from patients undergoing surgery for malignant GBM were used to investigate the expression of IL-22 and IL-22R by using quantitative RT-PCR, western blotting and confocal microscopy studies. The role of IL-22 in proliferation and survival of GBM cell lines was investigated in vitro by BrdU and ELISA cell death assays. We report herein that the two subunits of the IL-22R complex are expressed on human GBM cells. Their activation, depending on exogenous IL-22, induced antiapoptotic effect and cell proliferation. IL-22 treatment of GBM cells resulted in increased levels of phosphorylated Akt, STAT3 signaling protein and its downstream antiapoptotic protein Bcl-xL and decreased level of phosphorylated ERK1/2. In addition, IL-22R subunits were expressed in all the 10 tested primary cell lines established from GBM tumors. Our results showed that IL-22R is expressed on GBM established and primary cell lines. Depending on STAT3, ERK1/2 and PI3K/Akt pathways, IL-22 induced GBM cell survival. These data are consistent with a potential role of IL-22R in tumorigenesis of GBM. Since endogenous IL-22 was not detected in all studied GBM cells, we hypothesize that IL-22R could be activated by immune microenvironmental IL-22 producing cells.
Asunto(s)
Glioblastoma/metabolismo , Interleucinas/metabolismo , Receptores de Interleucina/metabolismo , Transducción de Señal , Línea Celular Tumoral , Proliferación Celular , Supervivencia Celular/genética , Expresión Génica , Glioblastoma/genética , Humanos , Subunidad beta del Receptor de Interleucina-10/genética , Subunidad beta del Receptor de Interleucina-10/metabolismo , Interleucinas/genética , Sistema de Señalización de MAP Quinasas , Células Madre Neoplásicas , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores de Interleucina/genética , Factor de Transcripción STAT3/metabolismo , Interleucina-22RESUMEN
During the past three decades, many studies have examined the capacity of embryonic neural grafts (dissociated cells or tissue blocks) to restore lost functions following various damages to the adult mammalian brain. Only very few focused on the visual system even if it is the optimal system to examine the potential of embryonic neural grafts in repairing point-to-point networks. Collectively, these studies show that, within limits, homologous sheets of fetal tissue grafted in the occipital cortex of adult rodents integrate into the host visual circuitry and are physiologically active.
Asunto(s)
Trasplante de Tejido Fetal , Feto/fisiología , Corteza Visual/fisiología , Corteza Visual/trasplante , Animales , Humanos , Vías Visuales/fisiologíaRESUMEN
Fetal neurons (embryonic age E16) of occipital origin grafted in the visual cortex of albino rats at increasing postnatal stages (P0, P7, P15, P30, P60, P120) can be activated by photic stimulation. Inputs originate from five major areas of the brain ipsilateral to the graft, namely, the claustrum, the periallocortex/proisocortex, the isocortex, the visual thalamus, and some unspecific subthalamic and hypothalamic nuclei. All inputs decrease in number with the age at which grafting was performed. Isocortical afferents exhibit furthermore a progressive laminar shaping. In neonates, layer II-III and layer V-VI neurons contribute equally to the graft input. In adults, grafts receive prominent input (approximately 70-80%) from layer VI neurons whereas layer II-III neurons account for less than 10%. Proportions of layer IV (approximately 2-4%) and layer V (approximately 15-20%) neurons innervating the graft remain stable, irrespective of the age of the recipient. The adult pattern of connectivity between the host brain and the graft establishes in frontal and temporal areas 1 week earlier than in occipital areas. It is nearly completed in postnatal day 15 (P15) grafted recipients. Supragranular neurons would be thus unable to innervate and to make stable synapses at the graft level beyond P15, i.e., when eyes open. Some infragranular neurons (supposedly remnants of the earliest generated cortical cell population) still have this capacity in adults.