Human Benign Prostatic Hyperplasia Stromal Cells As Inducers and Targets of Chronic Immuno-Mediated Inflammation

Abstract

Benign prostatic hyperplasia (BPH), a highly prevalent prostatic condition, could involve an inflammatory component in disease pathogenesis. In this study, we show that human stromal prostate cells obtained from BPH tissue can actively contribute to the inflammatory process by secreting proinflammatory cytokines as well as chemokines able to recruit lymphomonuclear cells and by acting as APCs. BPH cells express all of the TLRs and their ligation leads to the secretion of CXCL8/IL-8, CXCL10, and IL-6. In addition, BPH cells express costimulatory as well as class I and class II MHC molecules, which activate alloreactive CD4+ cells that in turn markedly up-regulate IL-12/IL-23p40 and IL-12p75 secretion by BPH cells. Alloreactive CD4+ cells activated by BPH cells secrete IFN-γ and IL-17. These cytokines up-regulate IL-6, IL-8, and CXCL10 production by BPH cells, creating a positive feedback loop that can amplify inflammation. IL-8 induces autocrine/paracrine proliferation of BPH cells, indicating also a growth-promoting activity of this chemokine in disease pathogenesis. These results show that human BPH cells represent nonprofessional APCs able to induce and sustain chronic inflammatory processes, supporting the relevance of inflammation in BPH pathogenesis.

Correlation between benign prostatic hyperplasia and inflammation

“…Different pathogens are described, including bacterial infections, urine reflux with chemical inflammation, dietary factors, hormones, autoimmune response [21][22][23], and a combination of these factors. As proposed by De Marzo et al [21], all of these mechanisms of chronic epithelial injury may be responsible for a decreased barrier function and facilitate the growth of infectious agents, with a chain reaction that further sustains and stimulates the inflammatory response and increases the prostatic inflammatory infiltrates.…”

Three-dimensional Imaging of Nociceptive Intraepidermal Nerve Fibers in Human Skin Biopsies

“…Biopsies are taken from the distal leg (DL), 10 cm above the lateral malleolus, and the proximal thigh (PT), 20 cm below the anterior iliac spine 9 . All IENF are labeled using protein gene product 9.5 (PGP), a pan neuronal marker [10][11][12] . At present, it is standard practice to diagnose small fiber neuropathies using IENFD determined by PGP staining with brightfield microscopy 6 .…”

Vitamin D Receptor Agonists in the Treatment of Benign Prostatic Hyperplasia

“…Thus, BPH can be seen as a form of chronic prostatitis, whose pathogenesis may be triggered by infection. Among the proinflammatory cytokines and chemokines produced by the prostatic microenvironment, stromal-derived IL-8 may be considered a key link between chronic inflammation and stromal cell proliferation [97]. The ability of VDR activation to inhibit inflammatory response both in prostatic and urethra smooth muscle cells seems to be related to the downregulation of the RhoA/ROCK signaling [64,73,86].…”

“…Prostatic stromal cells appear to play a critical role in the induction of inflammatory responses by activating CD4þ lymphocytes and favoring their differentiation into effector Th1 and Th17 cells [97]. Thus, BPH can be seen as a form of chronic prostatitis, whose pathogenesis may be triggered by infection.…”