interleukin-8 and Prostatic-Hyperplasia

Benign prostatic hyperplasia (BPH) is a common disorder affecting 50-80% of the aged male population. Androgens and age have been traditionally considered the main determinants of prostate enlargement, but in the last years a potentially important role of chronic inflammation in BPH pathogenesis has emerged. Bacterial and non-infectious chronic prostatitis could represent inciting factors leading to tissue hyperproliferation, possibly via the recently demonstrated antigen-presenting capacity of prostatic stromal cells, enabling them to induce and sustain intraglandular immune responses. The prostate growth-promoting chemokine IL-8 could represent a direct link between chronic prostate inflammation and autocrine/paracrine stromal cell proliferation, in agreement with its marked secretion induced in BPH stromal cells by a combination of Th1 and Th17 cell-derived inflammatory cytokines. BPH stromal cells express the vitamin D receptor (VDR), which is up-regulated by exposure to inflammatory stimuli. The non-hypercalcaemic VDR agonist elocalcitol, shown to arrest BPH development by decreasing the intra-prostatic androgen signalling without directly interfering with systemic androgen action, exerts immunoregulatory and anti-inflammatory properties in different prostatic pathology characterized by growth and inflammation. The mechanism of action of VDR agonists supports an important role of chronic inflammation in BPH pathogenesis and strengthens the concept of these agents as a therapeutic option for pharmacological treatment of BPH.

Topics: Androgens; Anti-Inflammatory Agents; Calcitriol; Chemokines; Chronic Disease; Cytokines; Humans; Inflammation; Interleukin-8; Male; Prostate; Prostatic Hyperplasia; Prostatitis; Receptors, Calcitriol; Signal Transduction; Stromal Cells

Metabolic syndrome (MetS) and benign prostate hyperplasia (BPH)/low urinary tract symptoms (LUTS) are often comorbid. Chronic inflammation is one of the putative links between these diseases. Phosphodiesterase type 5 inhibitors (PDE5i) are recognized as an effective treatment of BPH-related LUTS. One proposed mechanism of action of PDE5 is the inhibition of intraprostatic inflammation. In this study we investigate whether PDE5i could blunt inflammation in the human prostate.. Evaluation of the effect of tadalafil and vardenafil on secretion of interleukin 8 (IL-8, a surrogate marker of prostate inflammation) by human myofibroblast prostatic cells (hBPH) exposed to different inflammatory stimuli. We preliminary evaluate histological features of prostatic inflammatory infiltrates in BPH patients enrolled in a randomized, double bind, placebo controlled study aimed at investigating the efficacy of vardenafil (10 mg/day, for 12 weeks) on BPH/LUTS.. In vitro treatment with tadalafil or vardenafil on hBPH reduced IL-8 secretion induced by either TNFα or metabolic factors, including oxidized low-density lipoprotein, oxLDL, to the same extent as a PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. These effects were reverted by the PKG inhibitor KT5823, suggesting a cGMP/PKG-dependency. Treatment with tadalafil or vardenafil significantly suppressed oxLDL receptor (LOX-1) expression. Histological evaluation of anti-CD45 staining (CD45 score) in prostatectomy specimens of BPH patients showed a positive association with MetS severity. Reduced HDL-cholesterol and elevated triglycerides were the only MetS factors significantly associated with CD45 score. In the MetS cohort there was a significant lower CD45 score in the vardenafil-arm versus the placebo-one.

Topics: Aged; Aged, 80 and over; Carbolines; Cyclic GMP; Double-Blind Method; Humans; Imidazoles; Inflammation; Interleukin-8; Lower Urinary Tract Symptoms; Male; Middle Aged; Myofibroblasts; Phosphodiesterase 5 Inhibitors; Pilot Projects; Piperazines; Prostate; Prostatic Hyperplasia; Sulfones; Tadalafil; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are the most common prostate disorders in the UK, which cause considerable ill health in older men. Transperineal template prostate biopsy (TTPB) has emerged as a reliable procedure for the histopathological diagnosis of PCa and BPH due to its higher cancer detection rates. Although antiseptic preparation and antibiotic prophylaxis are used to ensure safety in patients undergoing surgical intervention, post-operative complications, such as infection and bleeding are still unavoidable, resulting in re-admissions, with resource implications. Currently, there is no biomarker profile to predict outcomes or monitor patients during the post-operative course. The main aim of this single-centre observational clinical pilot-study was to investigate the role of inflammatory and infection biomarkers following TTPB and their association with post-operative complications.. Forty-five patients scheduled for elective TTPB were recruited after informed consent at the Wrexham Maelor and Glan Clwyd Hospitals, North Wales, UK (n = 45). Prior to surgery, venous blood samples were collected at baseline and subsequently at 30, 120, and 240 min post-operatively. Urine samples were collected before and 120 min after the procedure. Serum procalcitonin (PCT), serum ferritin, and urine B. Following TTPB, significant (p ≤ 0.05) increases were observed in uB. Although not confirmative, changes seen in biomarkers such as uB

Topics: Aged; Anti-Infective Agents, Local; Biomarkers; Biopsy; Ferritins; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Male; Pilot Projects; Postoperative Complications; Procalcitonin; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Tumor Necrosis Factor-alpha

The clinical manifestation of benign prostatic hyperplasia (BPH) is causally linked to the inflammatory microenvironment and proliferation of epithelial and stromal cells in the prostate transitional zone. The CXC-chemokine interleukin-8 (IL-8) contributes to inflammation. We evaluated the expression of inflammatory cytokines in clinical specimens, primary cultures, and prostatic lineage cell lines. We investigated whether IL-8 via its receptor system (IL-8 axis) promotes BPH.. The messenger RNA and protein expression of chemokines, including components of the IL-8 axis, were measured in normal prostate (NP; n = 7) and BPH (n = 21), urine (n = 24) specimens, primary cultures, prostatic lineage epithelial cell lines (NHPrE1, BHPrE1, BPH-1), and normal prostate cells (RWPE-1). The functional role of the IL-8 axis in prostate epithelial cell growth was evaluated by CRISPR/Cas9 gene editing. The effect of a combination with two natural compounds, oleanolic acid (OA) and ursolic acid (UA), was evaluated on the expression of the IL-8 axis and epithelial cell growth.. Among the 19 inflammatory chemokines and chemokine receptors we analyzed, levels of IL-8 and its receptors (CXCR1, CXCR2), as well as, of CXCR7, a receptor for CXCL12, were 5- to 25-fold elevated in BPH tissues when compared to NP tissues (P ≤ .001). Urinary IL-8 levels were threefold to sixfold elevated in BPH patients, but not in asymptomatic males and females with lower urinary tract symptoms (P ≤ .004). The expression of the IL-8 axis components was confined to the prostate luminal epithelial cells in both normal and BPH tissues. However, these components were elevated in BPH-1 and primary explant cultures as compared to RWPE-1, NHPrE1, and BHPrE1 cells. Knockout of CXCR7 reduced IL-8, and CXCR1 expression by 4- to 10-fold and caused greater than or equal to 50% growth inhibition in BPH-1 cells. Low-dose OA + UA combination synergistically inhibited the growth of BPH-1 and BPH primary cultures. In the combination, the drug reduction indices for UA and OA were 16.4 and 7852, respectively, demonstrating that the combination was effective in inhibiting BPH-1 growth at significantly reduced doses of UA or OA alone.. The IL-8 axis is a promotor of BPH pathogenesis. Low-dose OA + UA combination inhibits BPH cell growth by inducing autophagy and reducing IL-8 axis expression in BPH-epithelial cells.

Topics: Cell Growth Processes; Cell Line; Cells, Cultured; Epithelium; Humans; Interleukin-8; Male; Oleanolic Acid; Prostate; Prostatic Hyperplasia; Receptors, CXCR; RNA, Messenger; Signal Transduction; Triterpenes; Ursolic Acid

Acute urinary retention (AUR) is one of the progressive manifestations of benign prostatic hyperplasia (BPH). This cross-sectional study was conducted to analyse the possible association between serum interleukin 8 (sIL-8) and AUR in BPH patients to provide evidence of sIL-8 as a potential biomarker for the prediction of AUR. The relationship between sIL-8 levels and AUR was evaluated by logistic regressions in 245 ageing Chinese men with BPH. The discriminant validity of sIL-8 and the optimal cut-off value were determined by a receiver operating characteristic curve. The levels of sIL-8 increased significantly in BPH patients with AUR (p < 0.001). The sIL-8 concentration was positively correlated with AUR in BPH patients (OR = 1.024, 95% CI: 1.009-1.040, p = 0.002). The correlation with AUR in the group with a high sIL-8 level (≥43.05 pg/ml) was significantly enhanced (OR = 8.853, 95% CI: 2.433-32.205, p = 0.001). The sIL-8 level correlated with AUR in Chinese BPH patients independently. As a possible predictor, sIL-8 may contribute to the screening of high-risk populations for AUR to create opportunities for the early effective interventions to improve prognosis and enhance the quality of life. Prospective studies are needed to support all these results.

Topics: China; Cross-Sectional Studies; Humans; Interleukin-8; Male; Prospective Studies; Prostatic Hyperplasia; Quality of Life; Urinary Retention

Benign prostatic hyperplasia (BPH) is a common multifactorial inflammatory disease of older men, defined by increased growth of prostate epithelial and stromal cells. Elevation serum levels of Interleukin-8 (IL-8), oxidative stress and inflammatory markers represent predictive surrogate markers of the disease progression in smoker BPH patients. A total of 86 BPH patients and 54 control subjects were admitted to the urology unit, Rizgary Teaching Hospital in Erbil City, Iraq between January and June 2020. Sera levels of prostate-specific antigen(PSA), IL-8, malondialdehyde (MDA), high sensitive C-reactive protein (hs-CRP), testosterone and some biomarkers concentrations were measured in the patients according to instructions of manufacturers. Patients and controls were categorized into groups according to smoking status (smokers and non-smokers). The sera levels of PSA, IL-8 and inflammatory markers like oxidative stress(MDA), hs-CRP and testosterone in every smoker subgroup (BPH patients and control) increased compared to the same non-smoker subgroups and significantly increased compared with non-smoker control (p<0.05). PSA demonstrated a significant positive correlation with the following terms, IL-8, MDA, hs-CRP, testosterone and low-density lipid (LDL)(p<0.05) and, insignificant negative correlation with high-density lipoprotein(HDL), (p>0.05). The current study demonstrated mounting evidence to support the role of smoking in the pathophysiology of BPH through elevation levels of inflammatory and oxidative stress biomarkers in sera of BPH patients.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Case-Control Studies; Humans; Inflammation; Interleukin-8; Kidney; Male; Malondialdehyde; Middle Aged; Oxidative Stress; Prostate-Specific Antigen; Prostatic Hyperplasia; Risk Factors; Smoking; Young Adult

Benign prostatic hyperplasia (BPH) is the most widespread urological disorder among elderly men. It is influenced by several factors, among which is the prostatic renin angiotensin system (RAS). Prostatic RAS activates several signaling pathways as proliferation, inflammation and angiogenesis that contribute to BPH development and progression. Captopril is a potent inhibitor of the angiotensin converting enzyme. Therefore, this study was performed to explore the potential protective effect of captopril against testosterone-induced BPH in rats. Male Sprague-Dawley rats were treated with either testosterone (3 mg/kg, s. c.) and/or captopril (100 mg/kg, orally) for four weeks. After treatments, prostatic serum markers and histopathology were assessed. Mechanistically, apoptotic, inflammatory and angiogenic pathways were examined. Testosterone significantly increased prostate weight, prostatic index, prostatic acid phosphatase and prostate specific antigen. These effects were almost prevented by captopril (100 mg/kg). Moreover, testosterone significantly elevated proliferating cell nuclear antigen and reduced Bax/Bcl-2 ratio, p53 and caspase-3 activity. Furthermore, it significantly elevated nuclear factor kappa-B, cyclooxygenase-II, tumor necrosis factor-α and interleukin-8. Besides, it caused a significant rise in vascular endothelial growth factor, basic fibroblast growth factor and matrix metalloproteinase-9. On the contrary, captopril effectively neutralised the proliferative, inflammatory and angiogenic effects of testosterone. Finally, the angiotensin-1 receptor expression in the BPH group was markedly decreased while captopril restored the receptor expression. Collectively, these findings indicate that captopril possesses a potent protective effect against testosterone-induced BPH via inducing apoptotic and suppressing inflammatory and angiogenic signaling pathways.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Fibroblast Growth Factor 2; Gene Expression Regulation; Interleukin-8; Male; Prostatic Hyperplasia; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Testosterone; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Prostate cancer (PCa) and benign prostate hyperplasia (BPH) as two prevalent age-related disorders in male have some shared genetic and immunological underlying mechanisms. However, researchers have aimed at identification of specific biomarkers with the ability to differentiate between these disorders. In the present study, we genotyped the rs4073, rs2227306 and rs1126647 single nucleotide polymorphisms within IL-8 gene in 530 individuals including 130 PCa patients, 200 BPH patients and 200 male controls. The rs2227306 alleles and genotypes were distributed equally in the three study groups. The frequency of the A allele of the rs4073 was significantly lower in PCa group compared with BPH group (OR (95% CI) = 0.62 (0.46-0.84), adjusted P value = 0.006). This allele was negatively associated with PCa risk in dominant model (OR (95% CI) = 0.53 (0.34-0.83), adjusted P value = 0.02). When comparing PCa and BPH groups, the rs1126647 was associated with PCa risk in recessive model (OR (95% CI) = 2.14 (1.23-3.72), adjusted P value = 0.02). The A T A haplotype (rs4073, rs2227306 and rs1126647 respectively) was less frequent in PCa group compared with BPH group (OR (95% CI) = 0.4 (0.22-0.75), adjusted P value = 0.03). Consequently, our data demonstrated significant differences in allele, genotype and haplotype frequencies of IL-8 variants between BPH and PCa patients which might imply distinct role for this chemokine in the pathogenesis of these disorders. Future studies are needed to elaborate the underlying mechanism of these observations.

Topics: Aged; Case-Control Studies; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Interleukin-8; Iran; Male; Middle Aged; Polymorphism, Single Nucleotide; Prostatic Hyperplasia; Prostatic Neoplasms

To investigate the expressions of interleukin-17 (IL-17) and interleukin-8 (IL-8) in benign prostatic hyperplasia (BPH) and BPH complicated with histological inflammation and their significance.. According to the results of HE staining, we divided 60 cases of BPH treated by transurethral resection of the prostate (TURP) into a BPH group (n = 23) and a BPH with inflammation group (n = 37). We analyzed the clinical data of the patients and determined the mRNA and protein expressions of IL-17 and IL-8 by immunohistochemistry, real-time fluorescence quantitative PCR, and Western blot, respectively.. Compared with the BPH patients complicated with inflammation, the BPH group showed significantly lower International Prostate Symptom Score (IPSS) (29.1 ± 6.2 vs 21.6 ± 3.7), quality of life score (QoL) (5.4 ± 1.3 vs 4.4 ± 1.6), postvoid residual urine volume (RUV) (［198.6 ± 15.5］ vs ［98.2 ± 19.3］ ml), prostate volume (［69.2 ± 24.1］ vs ［49.8 ± 16.5］ ml), PSA level (［7.4 ± 1.9］ vs ［2.8 ± 0.8］ μg/L) and serum c-reactive protein content (CRP) (［5.1±2.0］ vs ［1.5±0.6］ mg/L), but a higher maximum urine flow rate (Qmax) (［4.7 ± 2.1］ vs ［8.2 ± 1.8］ ml/s) (all P<0.05). The former group had a significantly higher incidence rate of urinary retention than the latter (32.4% ［12/37］ vs 8.69% ［2/23］), mRNA expressions of IL-17 (0.303 ± 0.076 vs 0.042 ± 0.019) and IL-8 (0.536 ± 0.059 vs 0.108 ± 0.025), and protein expressions of IL-17 (0.88 ± 0.10 vs 0.34 ± 0.05) and IL-8 (1.07 ± 0.08 vs 0.43 ± 0.04) (all P<0.05).. The expressions of IL-17 and IL-8 are upregulated in the prostatic tissue of the BPH patients with inflammation, which may play a significant role in the development and progression of BPH.. 目的： 探讨单纯良性前列腺增生（BPH）与伴有前列腺炎的BPH患者前列腺组织中IL-17和 IL-8表达差异。方法： 收集福建医科大学附属第一医院行经尿道前列腺电切术的60例BPH患者标本。根据标本HE染色不同分为单纯BPH组23例和合并炎症的BPH组37例。对两组患者的临床资料进行分析比较；用免疫组织化学方法检测各标本IL-17和IL-8的表达情况，用荧光定量PCR和Western印迹检测各标本IL-17和IL-8 mRNA和蛋白的表达。结果： 单纯BPH组和合并炎症的BPH组患者的国际前列腺症状评分（IPSS）［（21.6±3.7）分 vs （29.1±6.2）分］、生活质量评分（QoL）［（4.4±1.6）分 vs (5.4±1.3) 分］、最大尿流率（Qmax）［(8.2±1.8) ml/s vs (4.7±2.1) ml/s］、残余尿量（RUV）［(98.2±19.3) ml vs (198.6±15.5) ml］、前列腺体积［(49.8±16.5) ml vs (69.2±24.1) ml］、PSA［(2.8±0.8) μg/L vs (7.4±1.9) μg/L］和C反应蛋白（CRP）［(1.5±0.6) mg/L vs (5.1±2.0) mg/L］,两组相比差异明显，有统计学意义（P<0.05）；合并炎症的BPH组患者尿潴留的发生率［32.4%（12/37）］明显高于单纯BPH组［8.69%（2/23），P<0.05］；IL-17 mRNA和IL-8 mRNA在合并炎症的BPH组前列腺组织中的表达量(0.303±0.076和0.536±0.059)均明显高于单纯BPH组（0.042±0.019和0.108±0.025，P<0.05）；IL-17和IL-8蛋白在单纯BPH组和在合并炎症的BPH组患者前列腺组织中的蛋白表达(0.34±0.05 vs 0.88±0.10、0.43±0.04 vs 1.07±0.08)，两者相比差异显著，有统计学意义（P<0.05）。结论：IL-17和IL-8在合并炎症的BPH患者前列腺组织中的表达上调，其可能在BPH的发生发展中起重要作用。.

Topics: Disease Progression; Humans; Inflammation; Interleukin-17; Interleukin-8; Male; Organ Size; Prostate; Prostatic Hyperplasia; Quality of Life; RNA, Messenger; Transurethral Resection of Prostate; Treatment Outcome; Urinary Retention

To investigate the relationship between interleukin-8 levels in expressed prostatic secretion and expressions of basic fibroblast growth factor (bFGF) and Bcl-2 in benign prostatic hyperplasia (BPH).. A series of 50 consecutive patients diagnosed with BPH and scheduled for transurethral resection of the prostate (TURP) were included. Patients were divided into two groups, simple BPH and BPH with chronic prostatitis (CP). The grade of inflammatory changes in the prostate was then determined blindly by two experienced pathologists, according to the classification system. Expressed prostatic secretion (EPS) was collected right before TURP for IL-8 detection using ELISA kits. The resected prostatic tissue was harvested for immunohistochemistry to measure the expression of Bcl-2 and bFGF.. A total of 30 (60%) patients were confirmed to have prostatic histologic inflammation. The volume of the prostate in BPH with CP was obviously larger than that in simple BPH (P=0.022). The NIH chronic prostatitis symptom index (NIH-CPSI) and international prostate symptom score (IPSS) of BPH with CP were both higher than those of simple BPH (P<0.05). Significantly increased levels of IL-8 were observed in EPS obtained from BPH patients with CP (mean level, 43.29 ng/L), compared with patients with simple BPH (mean level, 36.90 ng/L) (P=0.003). The expression of Bcl-2 in BPH with CP (mean level, 6.17) increased significantly, compared with those in simple BPH (mean level, 2.45) (P=0.013). The expression of bFGF in BPH with CP (mean level, 7.57) also obviously elevated, compared with those in simple BPH (mean level, 5.05) (P=0.008). Correlation coefficients of IL-8 levels in EPS and expression of Bcl-2 or bFGF indicated that IL-8 had strong correlation with Bcl-2 and bFGF respectively both in simple BPH and BPH with CP (0

Topics: Chronic Disease; Fibroblast Growth Factor 2; Humans; Immunohistochemistry; Interleukin-8; Male; Prostatic Hyperplasia; Proto-Oncogene Proteins c-bcl-2

To investigate the correlation of the levels of interleukin-8 (IL-8) and IL-6 in the prostatic fluid with serum levels of serum prostate-specific antigen (PSA) in patients with benign prostatic hyperplasia (BPH) complicated by prostatitis.. A series of 211 patients undergoing surgery of BPH were divided into BPH group (n=75) and BPH with prostatitis group (n=136) according to the white blood cell count in the prostatic fluid. The clinical and laboratory findings were compared between the two groups, and stepwise regression analysis was used to assess the association of IL-8 and IL-6 with serum PSA level.. No significant differences were found in age, BMI, blood pressure, blood glucose, blood lipids, IPSS score, PSA-Ratio, or prostate volume between the two groups (P<0.05). The patients with prostatitis had significantly increased serum PSA and prostate fluid IL-8 and IL-6 levels compared with those without prostatitis (P<0.001). Multiple linear regression analysis showed that IL-8 and IL-6 levels and white blood cell count in the prostatic fluid were all positively correlated with serum PSA level.. Prostatitis is an important risk factor for elevated serum PSA level in patients with BPH, and both IL-8 and IL-6 levels in the prostatic fluid are correlated with serum PSA level.

Topics: Body Fluids; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatitis; Regression Analysis; Risk Factors

Trichomonas vaginalis causes the most prevalent sexually transmitted infection worldwide. Trichomonads have been detected in prostatic tissues from prostatitis, benign prostatic hyperplasia (BPH), and prostate cancer. Chronic prostatic inflammation is known as a risk factor for prostate enlargement, benign prostatic hyperplasia symptoms, and acute urinary retention. Our aim was to investigate whether T. vaginalis could induce inflammatory responses in cells of a benign prostatic hyperplasia epithelial cell line (BPH-1). When BPH-1 cells were infected with T. vaginalis, the protein and mRNA of inflammatory cytokines, such as CXCL8, CCL2, IL-1β, and IL-6, were increased. The activities of TLR4, ROS, MAPK, JAK2/STAT3, and NF-κB were also increased, whereas inhibitors of ROS, MAPK, PI3K, NF-κB, and anti-TLR4 antibody decreased the production of the 4 cytokines although the extent of inhibition differed. However, a JAK2 inhibitor inhibited only IL-6 production. Culture supernatants of the BPH-1 cells that had been incubated with live T. vaginalis (trichomonad-conditioned medium, TCM) contained the 4 cytokines and induced the migration of human monocytes (THP-1 cells) and mast cells (HMC-1 cells). TCM conditioned by BPH-1 cells pretreated with NF-κB inhibitor showed decreased levels of cytokines and induced less migration. Therefore, it is suggested that these cytokines are involved in migration of inflammatory cells. These results suggest that T. vaginalis infection of BPH patients may cause inflammation, which may induce lower urinary tract symptoms (LUTS).

Topics: Cell Line; Cell Movement; Chemokine CCL2; Humans; Inflammation; Interleukin-1beta; Interleukin-6; Interleukin-8; Lower Urinary Tract Symptoms; Male; Monocytes; Prostatic Hyperplasia; Trichomonas Infections; Trichomonas vaginalis

The objective of this study is to explore the effects of reactive oxygen species (ROS) under hypoxic environment in prostatic stromal cells (PSC).. To detect the expression of ROS in PSC and the tissues of benign prostatic hyperplasia (BPH) by flow cytometry; under hypoxic conditions, to observe the changes of cells growth and ROS in PSC; quantitative PCR was used to detect hypoxia inducible factor-1α (HIF-1α), androgen receptors (AR), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) in PSC; After edaravone intervening, to examine the changes of cells growth, ROS, HIF-1α, AR, VEGF, and IL-8 under hypoxic conditions.. The expression of ROS in tissues and cells which under hypoxic condition was significantly increased. 3% O2 promoted the proliferation. The HIF-1α, AR, VEGF, and IL-8 were upregulated under 3% O2. After edaravone intervening, ROS significantly decreased, HIF-1α and VEGF were downregulated, and cell proliferation declined.. Hypoxia stimulates the generation of ROS, and the ROS may play a key role in BPH.

Topics: Cell Proliferation; Flow Cytometry; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Interleukin-8; Male; Prostate; Prostatic Hyperplasia; Reactive Oxygen Species; Real-Time Polymerase Chain Reaction; Receptors, Androgen; Stromal Cells; Vascular Endothelial Growth Factor A

High prevalence of lower urinary tract symptoms (LUTS) consistent with benign prostate hyperplasia (BPH) is associated with obesity and prostatic inflammation. Here, we investigated whether chemokines associated with obesity and prostatic inflammation can be measured in normally voided urine of BPH/LUTS patients to demonstrate the mechanistic association between obesity and BPH/LUTS.. Frozen urine specimens of BPH/LUTS patients enrolled in the Nashville Men's Health Study were sent for blinded analysis to University of Pittsburgh. Thirty patients were blocked by their AUA-SI (>7 or ≤7) and prostatic enlargement (<40, 40-60, >60 cc). Clinical parameters including age, prostate size, and medications were derived from chart review. CXC chemokines (CXCL-1, CXCL-8, and CXCL-10), CC chemokines (CCL2 and CCL3), and sIL-1ra were measured in thawed urine using Luminex™ xMAP(®) technology and ELISA for NGF.. Urinary CCL2 levels were several fold higher compared with the other six proteins, of which CCL3 was detectable in less than one-fourth of patients. Urine levels of sIL-1ra and CXCL-8 were significantly associated with increasing BMI and waist circumference in BPH patients. CXCL-8 showed a marginal association with overall AUA-SI scores, as well as obstructive (p = 0.08) symptom subscores. Prostate volume was inversely and marginally associated with urinary CXCL-10 (p = 0.09).. Urine levels of CXCL-8, CXCL-10, and sIL-1ra were associated with varying degrees with LUTS severity, prostate size, and obesity, respectively. These findings in urine are consistent with past studies of chemokine levels from expressed prostatic secretions and demonstrate the potential of noninvasively measured chemokine in urine to objectively classify BPH/LUTS patients.

Topics: Adult; Chemokine CXCL10; Humans; Inflammation; Interleukin-8; Lower Urinary Tract Symptoms; Male; Middle Aged; Obesity; Prostate; Prostatic Hyperplasia; Statistics as Topic; Urine Specimen Collection

Benign prostatic hyperplasia (BPH) is characterized by increased tissue mass in the transition zone of the prostate, which leads to obstruction of urine outflow and considerable morbidity in a majority of older men. Senescent cells accumulate in human tissues, including the prostate, with increasing age. Expression of proinflammatory cytokines is increased in these senescent cells, a manifestation of the senescence-associated secretory phenotype. Multiplex analysis revealed that multiple cytokines are increased in BPH, including GM-CSF, IL-1α, and IL-4, and that these are also increased in senescent prostatic epithelial cells in vitro. Tissue levels of these cytokines were correlated with a marker of senescence (cathepsin D), which was also strongly correlated with prostate weight. IHC analysis revealed the multifocal epithelial expression of cathepsin D and coexpression with IL-1α in BPH tissues. In tissue recombination studies in nude mice with immortalized prostatic epithelial cells expressing IL-1α and prostatic stromal cells, both epithelial and stromal cells exhibited increased growth. Expression of IL-1α in prostatic epithelial cells in a transgenic mouse model resulted in increased prostate size and bladder obstruction. In summary, both correlative and functional evidence support the hypothesis that the senescence-associated secretory phenotype can promote the development of BPH, which is the single most common age-related pathology in older men.

Topics: Animals; Biomarkers; Cathepsin D; Cellular Senescence; Cytokines; Epithelial Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Interleukin-4; Interleukin-8; Male; Mice; Mice, Nude; Mice, Transgenic; Phenotype; Prostate; Prostatic Hyperplasia; Stromal Cells; Urinary Bladder Neck Obstruction

Red onion scales (ROS) contain large amounts of flavonoids that are responsible for the reported antioxidant activity, immune enhancement, and anticancer property. Atypical prostatic hyperplasia (APH) was induced in adult castrated Wistar rats by both s.c. injection of testosterone (0.5 mg/rat/day) and by smearing citral on shaved skin once every 3 days for 30 days. Saw palmetto (100 mg/kg) as a positive control and ROS suspension at doses of 75, 150, and 300 mg/kg/day were given orally every day for 30 days. All medications were started 7 days after castration and along with testosterone and citral. The HPLC profile of ROS methanolic extract displayed two major peaks identified as quercetin and quercetin-4'-β-O-D-glucoside. Histopathological examination of APH-induced prostatic rats revealed evidence of hyperplasia and inflammation with cellular proliferation and reduced apoptosis Immunohistochemistry showed increased tissue expressions of IL-6, IL-8, TNF-α, IGF-1, and clusterin, while TGF-β1 was decreased, which correlates with the presence of inflammation. Both saw palmetto and RO scale treatment have ameliorated these changes. These ameliorative effects were more evident in RO scale groups and were dose dependent. In conclusion, methanolic extract of ROS showed a protective effect against APH induced rats that may be attributed to potential anti-inflammatory and immunomodulatory effects.

Topics: Animals; Immunologic Factors; Interleukin-6; Interleukin-8; Male; Onions; Plant Extracts; Prostatic Hyperplasia; Rats; Rats, Wistar; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

To evaluate the therapeutic effect of Compound Xuanju Capsule (CXC) on autoimmune prostatitis in rat models.. Sixty healthy male Wistar rats were randomly divided into five groups of equal number: blank control, low-concentration purified prostate protein (low-conc PPP), low-conc PPP + CXC treatment, high-concentration PPP (hi-con PPP), and hi-conc PPP + CXC treatment. Autoimmune prostatitis models were established by intragastric administration of PPP solution at 15 mg/ml (low concentration) and 80 mg/ml, respectively. At 30 days after modeling, the rats in the blank control and low-conc and hi-conc PPP model groups were treated with normal saline, and those in the other two groups with CXC at a daily dose of 0.068 g/ml. At 30, 45, and 60 days, all the animals were sacrificed for observation of pathological changes in the prostate tissue and determination of the levels of IL-8, IL-10, and TNF-alpha in the serum.. Compared with the PPP models, the hi-conc PPP + CXC group showed significantly reduced levels of IL-8 and TNF-alpha in the serum at 45 days ([148.54 +/- 17.23] and [62.14 +/- 5.59] pg/ml vs [100.77 +/- 11.08] and [32.63 +/- 2.91] pg/ml, P < 0.05) and at 60 days ([143.69 +/- 17.28] and [59.38 +/- 5.50] pg/mlvs [95.77 +/-10.53] and [29.63 +/- 2.66] pg/ml, P < 0.05), and so did the low-cone PPP + CXC group at 45 days ([128.47 +/- 12.21] and [40.43 +/- 3.64] pg/ml vs [111.76 +/- 10.07] and [35.44 +/- 3.17] pg/ml, P < 0.05) and at 60 days ([131.07 +/- 10.93] and [43.34 +/- 3.91] pg/ml vs [97.46 +/- 8.75] and [30.44 +/- 2.75] pg/ml, P < 0.05). The serum level of IL-10 was remarkably elevated in the hi-cone PPP + CXC group as compared with that of the PPP models at 45 and 60 days ([189.14 +/- 16.78] and [184.14 +/- 15.89] pg/ml vs [230.48 +/- 29.96] and [248.48 +/- 31.03] pg/ml, P < 0.05), and so was it in low-cone PPP + CXC group ([223.14 +/- 17.87] and [224.14 +/- 17.93] pg/ml vs [231.42 +/- 23.18] and [249.42 +/- 24.97] pg/ml, P < 0.05). Pathological examination revealed morphological damages to the prostate tissue and infiltration of inflammatory cells in the model rats, but no obvious changes in the normal controls. At 15 days of treatment, the rats in the PPP + CXC group showed enlarged prostate glandular cavity, mild proliferation of epithelial cells, no obvious infiltration of inflammatory cells in the interstitial tissue, and a few visible fibrous tissues under the light microscope.. Compound Xuanju Capsule is efficacious on autoimmune prostatis in rats by reducing inflammatory changes in the prostate tissue and improving the expression of inflammatory factors.

Topics: Animals; Autoimmune Diseases; Capsules; Interleukin-10; Interleukin-8; Male; Prostatic Hyperplasia; Prostatic Secretory Proteins; Prostatitis; Random Allocation; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Topics: Carbolines; Humans; Imidazoles; Interleukin-8; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Prostate; Prostatic Hyperplasia

To investigate the correlation of International Prostate Symptom Score (IPSS) with the levels of interleukin-8 (IL-8) and cyclooxygenase-2 (COX-2) in the prostate tissue and expressed prostatic secretion (EPS) in patients with benign prostatic hyperplasia (BPH) complicated by prostatitis.. We divided 80 BPH patients to be treated by transurethral resection of the prostate (TURP) into a simple BPH group (n = 30) and a BPH with prostatitis group (n = 50) based on the pathologic features. We statistically analyzed IPSS and the levels of IL-8 and COX-2 in EPS before surgery and the IL-8 and COX-2 levels in the prostate tissue after surgery.. IPSS was positively correlated with the IL-8 and COX-2 levels in the prostate tissue and EPS of the BPH patients, moderately in the simple hyperplasia group (r > 0.5) and highly in the other (r > 0.8). The levels of IL-8 and COX-2 in the prostate tissue and EPS were significantly higher in the BPH with prostatitis group than in the simple BPH group (P < 0.05).. The levels of IL-8 and COX-2 in EPS indirectly reflect those in the prostate tissue. IPSS and the levels of IL-8 and COX-2 in EPS can help determine whether BPH is complicated by histological prostatic inflammation.

Topics: Aged; Aged, 80 and over; Cyclooxygenase 2; Humans; Interleukin-8; Male; Middle Aged; Prostate; Prostatic Hyperplasia; Prostatitis

To study the pathologic features and differences of tissue inflammation in benign prostatic hyperplasia (BPH) and prostate cancer (PCa).. The HE stained slice obtained by prostate biopsy from 143 BPH and 106 PCa were reviewed to determine whether the tissue inflammation existed. According to the histological classification of prostatic tissue inflammation, the features of tissue inflammation and the differences of these features between the two groups were studied in detail.. There were 142 cases found tissue inflammation in 143 BPH patients and 104 cases in 106 PCa patients, so the incidences of tissue inflammation in BPH and PCa were 99. 3% and 98. 1% respectively. The anatomical location of inflammation was significant difference between BPH and PCa group (P<0. 05). The peri-glandular inflammation (56. 3%) was primary in BPH, and interstitial inflammation (56.7%) was the main pattern in PCa. The inflammation range was also significant difference between the two groups (P<0. 05). The inflammation was presented multifocally (60. 6%) in BPH, and focal lesions (51. 0%) was commonly found in PCa. Mild inflammation was most frequently observed in both groups (P>0. 05). However, there were statistically significant differences between the two groups in the degree of moderate and severe inflammation (P<0. 05).. The incidences of tissue inflammation were high in both BPH and PCa, but the pathological features of tissue inflammation were different between BPH and PCa.

Topics: Adult; Aged; Aged, 80 and over; Biopsy; China; Complement C3; Humans; Inflammation; Interleukin-8; Male; Middle Aged; Prostatic Hyperplasia; Prostatic Neoplasms

Recently, it was reported that the soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) is secreted by microvascular endothelial cells from human BPH (HPECs). The purpose of this study was to investigate the modulation of sVEGFR-2 by common endothelial cell stimulators. In addition, the physiological role of sVEGFR-2 with regard to the VEGF-stimulated proliferation of HPEC was investigated.. HPECs were isolated and cultured from fresh BPH tissue. After the incubation of HPECs either with adenosine triphosphate (ATP), interleukin (IL)-6, IL-8 or IL-12, the secretion of sVEGFR-2 was measured by enzyme-linked immunosorbent assay. For measurement of HPEC proliferation influenced by sVEGFR-2, VEGF-stimulated HPEC was cultured with/without sVEGFR-2. Cell proliferation was assessed with the Alamar Blue method.. The sVEGFR-2 secretion was increased by ATP and decreased by IL-12 and IL-8, respectively. IL-6 did not show any significant effect on sVEGFR-2 secretion of HPECs. HPEC proliferation was significantly inhibited by sVEGFR-2.. In this study, our data suggest that the secretion of sVEGFR-2 by microvascular endothelial cells from prostate origin is influenced by multiple endothelial cell stimulators. Furthermore, our data suggest that sVEGFR-2 acts as an antiangiogenic factor.

Topics: Adenosine Triphosphate; Cell Proliferation; Cells, Cultured; Endothelium, Vascular; Humans; Interleukin-12; Interleukin-6; Interleukin-8; Male; Prostate; Prostatic Hyperplasia; Vascular Endothelial Growth Factor Receptor-2

Interleukin-8 (IL-8) is upregulated in fibrotic and malignant diseases and is a key mediator of proliferative responses. Elevated IL-8 was recently correlated with benign prostatic hyperplasia epithelium and a myofibroblast reactive stroma. Thus, we sought to determine whether overexpressed IL-8 and keratinocyte-derived chemokine (KC), the functional murine homolog of IL-8, induce prostate epithelial hyperplasia and a reactive phenotype.. Transgenic mice that overexpress KC within prostate epithelia and xenograft models with engineered human cells that overexpress IL-8 were developed.. Overexpression of KC in transgenic mice produced hyperplastic prostate epithelial acini associated with a periacinar reactive stroma. KC induced an altered epithelial/stroma proliferation index ratio, increased acini diameter, epithelial infolding, and expression of prototypical reactive stroma markers. Overexpression of IL-8 in normal human prostate epithelial xenografts correlated with elevated epithelial proliferation index and altered morphology. Elevated human prostate stromal and epithelial cell proliferation, nodule-like morphology and increased xenograft survival were observed in IL-8-overexpressing orthotopic xenografts.. Together, these data demonstrate that overexpression of IL-8/KC results in a prostate epithelial hyperplasia with an associated reactive stroma phenotype. The novel transgenic mouse and human xenograft models described here may be useful in dissecting key mechanisms of IL-8 induced prostate hyperplasia and reactive stroma.

Topics: Animals; Cell Line; Cell Proliferation; Chemokines; Disease Models, Animal; Epithelial Cells; Graft Survival; Humans; Interleukin-8; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Phenotype; Prostate; Prostatic Hyperplasia; Rats; Stromal Cells; Transplantation, Heterologous

Benign prostatic hyperplasia (BPH) is characterized by an important inflammatory component. Stimulation of human prostate stromal cells from BPH tissues with proinflammatory cytokines leads to secretion of IL-8, a chemokine involved in BPH pathogenesis. The vitamin D receptor (VDR) agonist elocalcitol can arrest prostate growth in BPH patients, but its mechanism of action in this pathology is still incompletely understood.. IL-8 levels were measured by real-time RT-PCR and ELISA. NF-kappaB translocation and COX-2 expression were evaluated by confocal microscopy. RhoA and Rho-kinase (ROCK) gene expression and functional activity were studied by real-time RT-PCR, immuno-kinase assays, Western blot analysis, confocal microscopy, and cell invasion.. Stimulation of BPH cells with IL-8 activates the calcium-sensitizing RhoA/ROCK pathway, as demonstrated by the increased membrane translocation of RhoA and by phosphorylation of the ROCK substrate myosin phosphatase target subunit 1 (MYPT-1). In agreement with these data, C3 exoenzyme, a selective RhoA inhibitor, inhibits IL-8-induced invasion of BPH cells. The VDR agonist elocalcitol significantly inhibits IL-8 production by BPH cells stimulated with inflammatory cytokines, and IL-8-induced proliferation of BPH cells. In addition, elocalcitol inhibits IL-8-induced membrane translocation of RhoA and MYPT-1 phosphorylation in BPH cells, and inhibits dose-dependently their IL-8-dependent invasion. The inhibition induced by elocalcitol of IL-8 production by BPH cells is accompanied by decreased COX-2 expression and PGE(2) production and by arrest of NF-kappaB p65 nuclear translocation, associated with inhibition of the RhoA/ROCK pathway.. These data provide a mechanistic explanation for the anti-proliferative and anti-inflammatory properties of elocalcitol in BPH cells.

Topics: Calcitriol; Cell Proliferation; Cells, Cultured; Cyclooxygenase 2; Dinoprostone; Humans; Inflammation; Interferon-gamma; Interleukin-17; Interleukin-8; Male; NF-kappa B; Prostatic Hyperplasia; Receptors, Calcitriol; rho-Associated Kinases; rhoA GTP-Binding Protein; Signal Transduction; Stromal Cells; Tumor Necrosis Factor-alpha

To evaluate the efficacy of interleukin-8 (IL-8) as a possible biomarker for diagnosis and treatment of benign prostatic hyperplasia (BPH) with chronic prostatitis. Histologic inflammation can be demonstrated in most BPH pathologic specimens. To provide objective parameters of inflammation, this prospective study quantified the IL-8 in expressed prostatic secretion (EPS) from BPH patients with or without histologic inflammation.. White blood cell (WBC) count and enzyme-linked immunosorbent assays of the EPS for IL-8 were done in 44 patients who underwent transurethral prostatic resection because of benign prostatic enlargement before the operations. The correlation between IL-8 and WBC count in EPS; prostatic specific antigen; and International Prostate Symptom Score, irritative, and obstructive subscores was determined by Pearson correlation analysis.. IL-8 was detectable in all patients (the threshold of detection for IL-8 is 5 pg/mL). Twenty-one (47.7%) BPH patients had chronic prostatitis. The mean level of IL-8 in EPS was higher in BPH with chronic prostatitis than in simple BPH (median +/- SE, 8175 +/- 3789 pg/mL vs 2806 +/- 1009 pg/mL). The catheter and age seemed to have no impact on the level of IL-8 in EPS. Statistically significant correlation was only found between IL-8 and WBC count. The sensitivity and specificity of IL-8 in EPS identifying the BPH with chronic prostatitis from the simple BPH were 85.7% and 91.3% respectively, at a cut-point of 3992 pg/mL.. IL-8 is significantly elevated in BPH patients with chronic prostatitis. IL-8 in EPS can serve as a reliable biomarker applicable to identifying BPH with chronic prostatitis from simple BPH.

Topics: Aged; Biomarkers; Chronic Disease; Humans; Interleukin-8; Male; Prostate; Prostatic Hyperplasia; Prostatitis; Transurethral Resection of Prostate

Prostate specific antigen (PSA) has been used as a screening test for the early detection of prostate cancer (PC) for many years. Although the introduction of PSA test led to a considerable increase in reported prostate cancer cases, there is still some controversy over the sensitivity and specificity of this marker in distinguishing PC patients from those with benign prostate hyperplasia (BPH), the most common benign prostate condition.. An attempt is made to elucidate if the plasma level of Interleukin 8 (IL-8) could be used effectively as a marker for the detection of prostate cancer.. Plasma levels of IL-8 and PSA were measured in two groups of 40 BPH and PC patients using enzyme-linked immunosorbent (ELISA) and radioimmunoassay (RIA) techniques, respectively. In addition IL-8 levels in PC3 and DU145 cell line supernatants were measured by ELISA technique.. The concentration of IL-8 in the plasma of PC patients was not significantly higher than the BPH subjects. Although, a correlation between plasma IL-8 concentration and the Gleason score of PC patients was found, no indicated correlation was detected between the concentration of IL-8 or PSA and age of the patients in both groups. DU145 and PC3 cell lines produced and secreted IL-8 in the media.. Data of this investigation collectively conclude no correlation between IL-8 concentration in PC and BPH patients.

Topics: Aged; Aged, 80 and over; Biomarkers, Tumor; Cell Line, Tumor; Diagnosis, Differential; Disease Progression; Humans; Interleukin-8; Male; Middle Aged; Prognosis; Prospective Studies; Prostate-Specific Antigen; Prostatic Hyperplasia; Prostatic Neoplasms

Prostasin is down-regulated during inflammation and in invasive cancers, and plays a role in regulation of inflammatory gene expression and invasion.. We used the human benign prostatic hyperplasia cell line BPH-1 to investigate gene expression changes associated with siRNA-mediated loss of prostasin expression. Quantitative PCR and/or western blotting were used to evaluate the expression changes of iNOS, ICAM-1, cyclin D1, IL-6, and IL-8. Gene expression changes were also evaluated in the presence of a PAR-2 antagonist. The PC-3 human prostate cancer cell line was used for evaluation of gene expression in response to prostasin re-expression.. Prostasin silencing in BPH-1 was associated with up-regulation of iNOS, ICAM-1, IL-6, and IL-8, and down-regulation of cyclin D1; as well as reduced proliferation and invasion. The iNOS up-regulation and cyclin D1 down-regulation associated with prostasin silencing were inhibited by a PAR-2 antagonist. Re-expression of prostasin, a serine active-site mutant, and a GPI-anchor-free mutant, in the PC-3 cells resulted in PAR-2 and cyclin D1 transcription up-regulation. Transcription up-regulation of IL-6 and IL-8 was associated with re-expression of the serine active-site mutant prostasin in the PC-3 cells. Transcription up-regulation of IL-8, but to a lesser extent, was also observed in PC-3 cells expressing the wild-type prostasin. Expression of a serine protease active prostasin, GPI-anchored or anchor-free, prevented the IL-6 induction in response to PAR-2. The GPI-anchor-free prostasin also prevented the IL-8 induction.. Prostasin plays a negative regulatory role on PAR-2-mediated signaling in prostate epithelial cells.

Topics: Blotting, Western; Cell Line; Cell Proliferation; Cyclin D1; Down-Regulation; Epithelial Cells; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Nitric Oxide Synthase Type II; Polymerase Chain Reaction; Prostate; Prostatic Hyperplasia; Receptor, PAR-2; RNA, Small Interfering; Serine Endopeptidases; Signal Transduction; Up-Regulation

Numerous inflammatory diseases display elevated interleukin (IL)-8, and most are associated with a reactive stroma. IL-8 expression is also elevated in benign prostatic hyperplasia (BPH), yet little is known about reactive stroma in BPH. Whether a reactive stroma response exists in BPH, whether this correlates with elevated IL-8, and whether IL-8 can induce a reactive stroma phenotype have not been determined. This study was designed to specifically address these issues.. Normal prostate transition zone tissue and BPH specimens, as identified by the Baylor College of Medicine pathology department, were examined by quantitative immunohistochemistry to correlate IL-8, smooth muscle alpha-actin, vimentin, calponin, and tenascin-C. In addition, human prostate stromal cell cultures were used to evaluate the effect of IL-8 on the expression of reactive stroma biomarkers.. BPH nodules exhibited elevated epithelial IL-8 immunoreactivity, and this correlated with elevated smooth muscle alpha-actin, reduced calponin, and altered deposition of tenascin-C, relative to the normal prostate transition zone tissue (P <0.05). Multiple vimentin-positive prostate stromal fibroblast cultures were induced by IL-8 to also co-express smooth muscle alpha-actin and tenascin-C, typical of a reactive stroma myofibroblast phenotype.. These data show that BPH reactive stroma is fundamentally different from normal prostate fibromuscular stroma and is typified by the emergence of a reactive stroma myofibroblast phenotype. This reactive stroma pattern correlated spatially with IL-8 elevation in adjacent epithelium. Additionally, IL-8 induced expression of myofibroblast markers in human prostate fibroblasts in vitro. These results suggest that IL-8 acts as a regulator of BPH reactive stroma and is therefore a potential therapeutic target.

Topics: Actins; Blotting, Western; Calcium-Binding Proteins; Calponins; Cell Line; Epithelium; Fibroblasts; Humans; Immunohistochemistry; Interleukin-8; Male; Microfilament Proteins; Phenotype; Prostate; Prostatic Hyperplasia; Stromal Cells; Tenascin; Vimentin

This prospective study quantified cytokine and chemokine levels in seminal plasma of patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and benign prostatic hyperplasia (BPH), to evaluate inflammatory mediators as possible surrogate markers for diagnosis and treatment efficacy.. Seminal plasma levels of eight cytokines and nine chemokines were evaluated by multiplex arrays in 83 men: 20 healthy controls and 9 men with CP/CPPS IIIA, 31 with CP/CPPS IIIB, and 23 with BPH. Prostate samples obtained by transurethral resection of the prostate from 13 patients with BPH were analysed by immunohistochemistry to detect interleukin 8 (IL-8)-producing cells and characterise inflammatory infiltrates.. Significantly increased levels of cytokines (IL-1alpha, IL-1beta, IL-6, IL-10, IL12p70) and chemokines (CCL1, CCL3, CCL4, CCL17, CCL22, CXCL8/IL-8) were observed in seminal plasmas from patients with CP/CPPS or BPH. However, only IL-8 was significantly elevated compared to controls (median [quartiles] 1984 [1164-2444] pg/ml), in patients with CP/CPPS IIIA (15,240 [10,630-19,501] pg/ml; p<0.0001), CP/CPPS IIIB (2983 [2033-5287] pg/ml; p=0.008), and BPH (5044 [3063-11,795] pg/ml, p<0.0001), discriminating CP/CPPS IIIA versus IIIB (accuracy=0.882+/-0.078; p=0.001). Inflammatory infiltrates were detected in prostate samples from 13 of 13 BPH patients, and IL-8-producing prostate cells in 11 of 13 samples. IL-8 concentration in seminal plasma was positively correlated with symptom score and prostate-specific antigen levels both in CP/CPPS and BPH patients.. IL-8 is expressed in situ by epithelial and stromal prostate cells and is functional, as shown by recruitment of cells expressing cognate receptors in BPH prostate tissue, indicating its involvement in disease pathogenesis. Among all the cytokines and chemokines analysed, IL-8 appears to be the most reliable and predictive surrogate marker to diagnose prostate inflammatory conditions, such as CP/CPPS and BPH.

Topics: Adult; Biomarkers; Chemokines; Cytokines; Humans; Interleukin-8; Male; Middle Aged; Predictive Value of Tests; Prostatic Hyperplasia; Prostatitis; Semen

The complexity of acute and chronic inflammatory processes may either lead to benign prostate hyperplasia (BPH) and/or prostate cancer. Obviously, various tissue cells are activated by chemokines via different chemotaxin receptors which then trigger subsequent processes in angiogenesis, cellular growth, and extravasation as well as neoplasia.. Using the surgically obtained tissue of patients (n = 36) with BPH or prostate carcinoma (PCA), we studied among others the expression of chemokines (Rantes, IL-8), chemotaxin receptors (CXCR-3 and -4, CCR-3, CCR-5), of matrixmetalloproteinases (MMP-2 and 9), of Toll-like (TL) receptors 1, 2, 3, 4, 5, 7, and 9 and of the inducible cyclooxygenase-2 (cox-2) by RT-PCR. Further support for the different properties of tissue from PCA was obtained using two different PCA cell lines (PC3 = androgen resistant cell) or LNCAP cells (androgen sensitive) with emphasis on IL-8, Il-6, and PGE(2) release. Cell lines were stimulated with either the tumor necrosis factor-alpha (TNF-alpha) and lipopolysacharide (LPS) over time. In addition to cytokine release, the quantification of mRNA by lightcycler for cox-2, IL-6, and IL-8 was performed on these cell lines.. Remarkable differences in expression were obtained by RT-PCR when BPH tissue versus PCA was analyzed. Expression of CXCR-1 after incubation with LPS and TNF-alpha showed time-dependent differences for androgen-sensitive LNCAP as compared to androgen-resistant PC-3 cells. TNF-alpha incubation leads to a time-dependent induction of cox-2 expression unlike to activation with LPS. Differences with regard to cox-2, IL-6, and IL-8 expression were seen by quantitative lightcycler analysis. Significant differences were also observed when TL receptors 4, 5, 7, and 9 were analyzed which were significantly expressed in BPH- as compared to PCA-tissue.. Our data clearly demonstrate that various inflammatory and cell biological cascades are involved which either lead to BPH or can be linked to the development of PCA. The exact cell biological mechanisms may provide novel therapeutic options in the treatment of both diseases.

Topics: Acute Disease; Aged; Aged, 80 and over; Cell Transformation, Neoplastic; Chemotactic Factors; Chronic Disease; Cyclooxygenase 2; Cytokines; Gene Expression Regulation, Neoplastic; Humans; Inflammation; Interleukin-6; Interleukin-8; Isoenzymes; Lipopolysaccharides; Male; Membrane Proteins; Middle Aged; Neovascularization, Pathologic; Prostaglandin-Endoperoxide Synthases; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Interleukin-8A; Reverse Transcriptase Polymerase Chain Reaction; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Benign prostatic hyperplasia (BPH) is an extremely common disease of older men characterized by increased growth of prostatic epithelial and stromal cells. Previously we showed that senescent epithelial cells accumulate in the prostate of aging men and secrete interleukin-1 alpha (IL-1 alpha). IL-8 is also present at increased levels in BPH tissues and induces expression of FGF2, a potent stromal growth factor. Therefore, we sought to determine if IL-8 is also expressed at increased levels by senescent epithelial cells and if this secreted IL-8 plays a role in the pathogenesis of BPH.. Expression of IL-8 in human BPH tissue and primary cultures of prostatic epithelial cells was analyzed using an enzyme-linked immunoabsorption assay (ELISA). Tissue senescence was assessed by a quantitative assay for senescence-associated beta galactosidase (SA-beta gal). Proliferation of primary and immortalized prostatic epithelial cells in response to IL-8 was determined by counting of cells at intervals after addition of IL-8.. Expression of IL-8 is significantly increased in vitro when cultured prostatic epithelial cells undergo senescence. Quantitative assay of BPH tissue extracts revealed that tissue IL-8 levels are correlated with both SA-beta gal activity and prostate weight. IL-8 promotes proliferation of primary and immortalized prostatic epithelial cells in culture.. Senescence of prostatic epithelial cells results in increased expression of IL-8, which can promote proliferation of non-senescent epithelial and stromal cells by direct and indirect mechanisms, and in this manner contributes to the increased tissue growth seen in BPH.

Topics: Cellular Senescence; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Humans; Interleukin-8; Male; Prostate; Prostatic Hyperplasia; Tumor Cells, Cultured

To investigate factors involved in inflammation of the prostate besides IL-15, we screened prostatic cells and tissues for IL-17 and IL-17 receptor expression.. Normal prostate (n = 1), BPH (n = 19), and carcinoma (CaP, n = 12) specimens were screened for IL-17, IL-17 receptor, CD45, IL-6, and IL-8 mRNA expression. The carcinoma cell lines DU145, PC3, LNCaP, and BPH-epithelial (EC), stromal cell (SC) preparations, and BPH-T-cell lines were analyzed for IL-17 production by RT-PCR and ELISA. The effect of IL-17 on IL-6, IL-8, TGF-beta1, and fibroblast growth factor (FGF-2) mRNA expression and/or release of SC was analyzed using real-time PCR and/or ELISA. Immunohistochemistry was used to localize both IL-17 and IL-17 receptor.. In the normal prostate, IL-17 expression was very weak and restricted to lymphocytes. In 79% of BPH and 58% of CaP specimens, IL-17 mRNA and protein expression was increased. IL-17 mRNA expression could be shown for activated BPH-T-cells and to some extend for BPH-EC. Expression of IL-17 receptor was ubiquitous. Release of IL-17 was shown only for activated BPH-T-cells. IL-17 stimulated expression of IL-6 (13-fold) and IL-8 (26-fold) by prostatic BPH-SC. In situ, however, the amount of IL-17mRNA in BPH-tissue did not correlate with the amount of IL-6 and IL-8 mRNA. In CaP tissue, significant correlation was found only between the amount of IL-6 and IL-8 mRNA.. Activated BPH-T-cells abundantly express IL-17. The increase of IL-17 in BPH-tissues goes hand in hand with elevated levels of IL-15, a pro-inflammatory cytokine with T-cell growth factor properties. A clinical relevance of increased IL-17 expression under pathological conditions is suggested by the demonstration of significant upregulation of IL-6 and IL-8 production of prostatic SC by IL-17.

Topics: Adult; Carcinoma; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation, Neoplastic; Homeostasis; Humans; Immunohistochemistry; Inflammation; Interleukin-17; Interleukin-6; Interleukin-8; Male; Polymerase Chain Reaction; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Interleukin; Receptors, Interleukin-17; Recombinant Proteins; RNA, Messenger; Up-Regulation

Benign prostatic hyperplasia (BPH) is an extremely common disease of older men in which there is benign overgrowth of the prostatic transition zone, leading to obstruction of urine outflow. Fibroblast growth factor (FGF) 2, a potent growth factor for prostatic stromal and epithelial cells, is increased twofold in BPH and its concentration is correlated with stromal proliferation in this condition. Immunohistochemistry of normal and hyperplastic prostate revealed that FGF2-expressing stromal cells were present in higher numbers near the epithelial acini, implying that epithelial cells may express a factor that induces FGF2 expression by stromal cells. Conditioned medium from primary cultures of prostatic epithelial cells was capable of inducing increased expression of FGF2 by primary stromal cultures. Blocking experiments with neutralizing anti-interleukin (IL)-8 antibodies and pretreatment with lipopolysaccharide, which down-regulates the IL-8 receptor, show that this inducing activity is because of the presence of IL-8 in the epithelial-conditioned medium. Analysis of normal prostatic peripheral zone and BPH tissue by enzyme-linked immunosorbent assay reveals that IL-8 is present at increased levels in hyperplastic prostate. Therefore IL-8 produced by prostatic epithelial cells can induce FGF2, a potent stromal and epithelial growth factor, and in this manner promote the abnormal proliferation of the prostatic transition zone that is critical in the pathogenesis of BPH.

Topics: Cells, Cultured; Epithelial Cells; Epithelium; Fibroblast Growth Factor 2; Humans; Interleukin-8; Male; Paracrine Communication; Prostate; Prostatic Hyperplasia; Reference Values; RNA, Messenger; Stromal Cells

Chronic prostatitis/chronic pelvic pain syndrome (CPPS) is a disorder characterized by pelvic pain and varying degrees of inflammation exhibited in expressed prostatic secretions (EPS). To provide objective parameters of inflammation, we measured the cytokines interleukin 8 (IL-8) and epithelial neutrophil activating peptide 78 (ENA-78) in EPS of healthy men, men with benign prostatic hyperplasia (BPH), men with bacterial prostatitis (BP), and men with chronic prostatitis/CPPS.. Enzyme-linked immunosorbent assays of the EPS for IL-8 and ENA-78 were done in 63 men: control (n = 9), BPH (n = 6), BP (n = 3), inflammatory CPPS (National Institutes of Health [NIH] category IIIa) (n = 17), noninflammatory CPPS (NIH category IIIb) (n = 17), and asymptomatic inflammatory prostatitis (NIH category IV) (n = 11).. IL-8 was detectable in all patients, and ENA-78 was detectable in all except 2 patients (threshold of detection 10 pg/mL for IL-8, 15 pg/mL for ENA-78). Mean levels of IL-8 [ENA-78] were similar in control (3010 pg/mL [423 pg/mL]), BPH (3341 pg/mL [98 pg/mL]), and IIIb (2751 pg/mL [335 pg/mL]) groups. Both cytokine levels were higher in BP (11,175 pg/mL [13,761 pg/mL]), IIIa (10,418 pg/mL [2240 pg/mL]), and IV (8571 pg/mL [1865 pg/mL]) groups. A statistically significant difference between the control group versus BP, IIIa, and IV (P <0.05) groups was found for IL-8 but not for ENA-78.. IL-8 and ENA-78 are frequently elevated in the EPS of men with BP, CPPS IIIa, and asymptomatic inflammatory prostatitis category IV. These cytokines are direct mediators of leukocyte accumulation and activation at inflammatory sites and may be responsible, in part, for the presence of inflammatory reaction in the prostate.

Topics: Adult; Aged; Bacterial Infections; Bodily Secretions; Chemokine CXCL5; Chemokines, CXC; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Humans; Interleukin-8; Male; Middle Aged; Pelvic Pain; Prostate; Prostatic Hyperplasia; Prostatitis

Using arbitrarily primed polymerase chain reaction (AP-PCR) ribonucleic acid (RNA) fingerprinting, we discovered a messenger RNA (mRNA) that encoded the cytokine interleukin-8 (IL-8) that was up-regulated in the peripheral blood leukocytes (PBLs) of patients with metastatic prostate cancer (CaP) compared with similar cells from healthy individuals. We compared the total prostate-specific antigen (PSA) levels, the free/total (f/t) PSA ratios, and the immunoreactive IL-8 serum concentrations in patients with either biopsy-confirmed benign prostatic hyperplasia (BPH) or CaP.. The sera from 35 apparently healthy normal volunteers and 146 patients with biopsy-confirmed BPH and CaP obtained from two academic centers were retrospectively examined to determine the serum levels of IL-8, total PSA (tPSA), and the f/t PSA ratio. Logistic regression and trend analysis statistical methods were used to assess the results.. Normals (n = 35), BPH patients (n = 53), patients with clinical Stages A to C CaP (n = 81), and patients with metastatic CaP (n = 1 2) had mean levels of IL-8 of 6.8, 6.5, 15.6, and 27.8 pg/mL, respectively. The IL-8 serum concentrations correlated with increasing CaP stage and also differentiated BPH from clinical Stages A, B, C, or D CaP better than tPSA and performed similarly to the f/t PSA ratio. The combination of the IL-8 levels and f/t PSA ratios using multivariate logistic regression analysis distinguished BPH from Stages A, B, C, or D CaP or only Stages A and B with a receiver operating characteristic area under the curve of 89.8% and 87.5%, respectively (P <0.0001).. The IL-8 serum concentration in our clinically well-defined patient sample was independent of the f/t PSA ratio as a predictor of CaP. When test samples are controlled for extraneous clinical origin of inflammation or infection, the combination of the IL-8 and f/t PSA assay results may offer an improved approach for distinguishing BPH from CaP.

Topics: Adult; Aged; Aged, 80 and over; Humans; Interleukin-8; Logistic Models; Male; Middle Aged; Prostatic Hyperplasia; Prostatic Neoplasms; RNA; ROC Curve; Sensitivity and Specificity