RESUMO
The majority of patients with benign prostate hyperplasia (BPH) exhibit chronic prostate inflammation and the extent of inflammation correlates with the severity of symptoms. How inflammation contributes to prostate enlargement and/or BPH symptoms and the underlying mechanisms are not clearly understood. We established a unique mouse model Prostate Ovalbumin Expressing Transgenic 3 (POET3) that mimics chronic non-bacterial prostatitis in men to study the role of inflammation in prostate hyperplasia. After the injection of ovalbumin peptide-specific T cells, POET3 prostates exhibited an influx of inflammatory cells and an increase in pro-inflammatory cytokines that led to epithelial and stromal hyperplasia. We have previously demonstrated with the POET3 model that inflammation expands the basal prostate stem cell (bPSC) population and promotes bPSC differentiation in organoid cultures. In this study, we investigated the mechanisms underlying the impact of inflammation on bPSC. We found that AR activity was enhanced in inflamed bPSC and was essential for bPSC differentiation in organoid cultures. Most importantly, we identified, for the first time, interleukin 1 receptor antagonist (IL-1RA) as a key regulator of AR in basal stem cells. IL-1RA was one of the top genes upregulated by inflammation and inhibition of IL-1RA abrogated the enhanced AR nuclear accumulation and activity in organoids derived from inflamed bPSC. The mirroring effects of IL-1RA recombinant protein and IL-1α neutralizing antibody suggest that IL-1RA may function by antagonizing IL-1α inhibition of AR expression. Furthermore, we established a lineage tracing model to follow bPSC during inflammation and under castrate conditions. We found that inflammation induced bPSC proliferation and differentiation into luminal cells even under castrate conditions, indicating that AR activation driven by inflammation in bPSC is sufficient for their proliferation and differentiation under androgen-deprived conditions. However, proliferation of the differentiated bPSC in the luminal layer significantly diminished with castration, suggesting inflammation may not maintain AR activity in stromal cells, as stromal cells deprived of androgen after castration could no longer provide paracrine growth factors essential for luminal proliferation. Taken together, we have discovered novel mechanisms through which inflammation modulates AR signaling in bPSC and induces bPSC luminal differentiation that contributes to prostate hyperplasia.
RESUMO
BACKGROUND: The aim of this study was to examine p53 and Ki-67 expression in relation to high grade dysplasia (HGD) clinical behaviour. METHODS: A retrospective, cross sectional study was conducted on mucosal biopsies from the stomach of 38 consecutive cases of HGD (25 males, average age: 57.5). The studied samples are represented by gastric biopsies obtained in course of gastroscopy for dyspepsia (at least 8 biopsies). HGD diagnosis was done by experienced pathologists (MC, DG) according to Goldstein's criteria. There were 12 non-dysplastic controls (7 males, average age: 49.4). The immunohistochemical study has been led with the utilization of a p53-antibody. For the cell proliferation assay, the sections were incubated with the MM1 monoclonal antibody. The clinical outcome subdivision of HGD was effected using the criteria of Rugge et al. For the classification of gastric cancer (GC): UICC TNM. RESULTS: p53 positivity has been evidenced in 65.5% of cases, while hyperproliferation in 100% of cases. That independently of the clinical behaviour. CONCLUSIONS: p53 positivity has been found only in part of the HGD cases and moreover a number of HGD with low or absent p53 scores has been found associated with high proliferation indices independently of the clinical evolution. This dissociation of cell kinetics and p53 expression suggests that other genetic events contributing to unregulate cell proliferation may occur in these lesions.
Assuntos
Dispepsia/imunologia , Dispepsia/patologia , Mucosa Gástrica/patologia , Antígeno Ki-67/análise , Neoplasias Gástricas/imunologia , Proteína Supressora de Tumor p53/análise , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
In the present study 60 cases age ranging from 18-40 years were studied for variation in the absolute basophil count on the different days of menstrual cycle. At the time of ovulation a statistically significant decrease in the number of basophil count was noted. The decrease in the number of basophil at mid cycle coincided with the irregular follicle seen by sonography, which indicated ovulation. The basophil count then increased during the luteal phase. Basopenia at the time of ovulation was probably due to migration of these cells from the peripheral blood towards the rupturing follicle for the release of histamine required for ovulation.