Inflammation Impacts Androgen Receptor Signaling in Basal Prostate Stem Cells Through Interleukin 1 Receptor Antagonist.

Autor: Cooper PO; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA.; These authors contributed equally to the manuscript., Yang J; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA.; These authors contributed equally to the manuscript., Wang HH; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA.; These authors contributed equally to the manuscript., Broman MM; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA., Awdalkreem GD; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA., Cresswell GM; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA., Wang L; Department of Pharmacology and Toxicology, Department of Urology, Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Goossens E; Department of Statistics, Purdue University, West Lafayette, IN 47907, USA., Lanman NA; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA., Doerge RW; Department of Statistics, Purdue University, West Lafayette, IN 47907, USA., Zheng F; Department of Statistics, Purdue University, West Lafayette, IN 47907, USA., Cheng L; Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Crist SA; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA., Braun RE; The Jackson Laboratory, Bar Harbor, ME 04609, USA., Jerde TJ; Department of Pharmacology and Toxicology, Department of Urology, Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA., Ratliff TL; Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47907, USA.; Purdue Institute for Cancer Research, West Lafayette, IN 47907, USA.
Jazyk: angličtina
Zdroj: Research square [Res Sq] 2023 Dec 15. Date of Electronic Publication: 2023 Dec 15.
DOI: 10.21203/rs.3.rs-3539806/v1
Abstrakt: 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.
Databáze: MEDLINE
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