Development and Characterization of a Transgenic Mouse Model of Cytokine-Mediated Prostate Inflammation.

摘要

A causal link between prostate inflammation and prostate diseases including prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer is unclear. This can be attributed to the fact that prostate inflammation is an extremely common histological finding. However, epidemiological, histopathological and molecular evidence suggest that inflammation may play a causal role in prostatitis, BPH and prostate adenocarcinoma. Discerning molecular mechanisms of chronic inflammation is almost impossible to do in humans. However, a physiologically relevant mouse model that encompasses prostate inflammation and its sequela could be highly informative. In this study, an innovative mouse model was developed that allows inducible expression of Interleukin 1beta. Interleukin 1beta is a proinflammatory cytokine implicated in major diseases including solid tumors, autoimmune disorders and neurodegenerative disorders. This potent cytokine is implicated in chronic prostatitis and is suggested to be a key mediator of pain. The IL-1beta-Mediated Inflammation Model (IMPI) characterized in this study, is based on the Tet-On technology, and therefore, is doxycycline inducible. Here, we report the development and characterization of the IMPI model, including the inflammatory phenotype and induction kinetics. The basic approach used to establish this model can be extended to other cytokines/chemokines implicated in prostate disease. Furthermore, we established the role of IL-1beta in mediating pelvic hypersensitivity that can be attenuated with IL-1beta-blockade. Most importantly, we determined that the model recapitulates histopathological features of human inflammatory and pre-neoplastic lesions. This study provides evidence to support the notion that IL-1beta-mediated chronic inflammation can induce pre-neoplastic lesions in the mouse prostate epithelium. Lastly, the genome-wide RNA expression changes mediated by IL-1beta induced prostate inflammation were identified. Pathways involved in inflammation, apoptosis, oxidative stress and chemokine signaling were determined. The IMPI model is a novel platform to test anti-inflammatory therapies and will aid in the development of novel inflammatory biomarkers.