Influence ofE. coli-induced prostatic inflammation on expression of androgen-responsive genes and transforming growth factor beta 1 cascade genes in rats

Abstract

Background Prostatic inflammation is reportedly associated with the development of prostatic hyperplasia. We investigated the effects of prostatic inflammation on expression levels of androgen-responsive genes and growth factors in the rat prostate. Methods Prostatic inflammation was induced by Escherichia coli (strain 1677) injection (0.2 mL of 1 × 108 CFU/mL) into the prostatic urethra of male Sprague-Dawley rats, and ventral lobes of the prostate were harvested on day 84. Rats were given 10 mg/kg celecoxib during the last month in the COX-2 inhibitor treated group. Histopathology and multiplex ELISA for inflammation-related proteins were performed. Glandular epithelial cells and stromal regions were separately isolated using laser-capture microdissection (LCM). Real-time RT-PCR was performed to examine mRNA levels of androgen-responsive genes in the epithelium and TGF-β1 cascade genes in the stroma. Results Hematoxylin and eosin staining showed that mild inflammation was distributed diffusely throughout the prostate. Polymorphonuclear cells infiltrated the slightly edematous stroma, but no morphological changes were observed in the epithelium. Immunohistochemically, expression of androgen receptor and TGF-β1 in addition to IL-6 and COX-2 were enhanced in the E. coli inoculated rats. All of these factors were suppressed in the celecoxib-treated rats. Upregulation of IL-1α, IL-1β, IL-6, and RANTES in the E. coli-inoculated rats was normalized by celecoxib treatment. Significant upregulation of androgen receptor and androgen-responsive genes such as Eaf2, ELL2, FKBP5, calreticulin and ornithine decarboxylase was observed in the LCM-dissected epithelium. Also TGF-β1 and its downstream cascade genes such as Hic-5, collagen 1, and fibronectin were upregulated significantly in the LCM-dissected stroma. The COX-2 inhibitor treatment suppressed upregulation of these genes. Conclusions Prostatic inflammation changed the expression of androgen-responsive genes in the epithelium and TGF-β1 cascade genes in the stroma. Activation of TGF-β1 cascade genes in the inflamed stroma, as well as altered androgen-responsive gene expression in the epithelium, might be involved in the development of BPH.

Association of anti‐inflammatory and antiangiogenic therapies negatively influences prostate cancer progression in TRAMP mice

“…According to Pan et al, COX‐2 selective anti‐inflammatory agents, such as celecoxib, may be powerful inhibitors of AR expression and functions in prostatic tumor cells. More recent studies corroborated the positive correlation between COX‐2 and AR levels during inflammation and also showed the upregulation of androgen‐responsive genes in this milieu, whereas celecoxib treatment was capable of reversing these effects . Our research group has also registered such celecoxib‐dependent anti‐androgen actions and showed that AR immunolabeling and protein expression were reduced following earlier celecoxib treatment in TRAMP mice from 8 to 12 weeks old .…”

“…Accordingly, nintedanib has shown ability to inhibit early intracellular signaling induced by TGF‐β and other TGF‐β‐activated non‐canonical pathways that also contribute to myofibroblast differentiation in this disease setting . In parallel, celecoxib also displayed antagonistic actions on TGF‐β signaling and expression during colorectal cancer and prostatitis . In different rodent models of prostatic inflammation, both TGF‐β reactivity and the expression of TGF‐β and its downstream cascade genes were decreased in the stroma following celecoxib administration .…”

“…LGPIN foci showed incidence of 65 Table 1). On the other hand, nintedanib treatment led to a significant decrease on the occurrence of WDAC foci, resulting in 0.88% incidence for this malignant lesion (P < 0.05) ( Figure 4D; Table 1).…”

Androgen receptor activation integrates complex transcriptional effects in osteoblasts, involving the growth factors TGF-β and IGF-I, and transcription factor C/EBPδ

“…Other recent studies revealed that TGF-β can activate AR in the absence of DHT and, as we show here in osteoblasts, it can cooperate with and enhance AR activation in response to DHT (Yang et al, 2014). Finally, within the context of inflammation, there are significant changes in the expression of both AR dependent and TGF-β dependent genes by prostate cells, perhaps leading to hyperplasia in that tissue (Funahashi et al, 2015). Local PGE2 levels are likely to be high in the inflamed prostate, and these findings may there relate at least in part to the individual and combined interactions that we note in our current study.…”

Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia

“…Since high expression of ELL2 has been reported in the prostate (Uhlen, et al 2005), ELL2 may be important for prostate homeostasis. ELL2 was also found to be an androgen response gene (Nelson, et al 2002; Bolton, et al 2007) that is up-regulated in response to chronic prostatic inflammation in rats (Funahashi, et al 2015) and was up-regulated in human benign prostatic hyperplasia (BPH) (O’Malley, et al 2009). The specific role of ELL2 in the prostate has not been fully elucidated; however, transfected ELL2 protein has been shown to interact with the potential prostate tumor suppressor gene ELL-associated factor 2 (EAF2) (Simone et al 2003).…”