CD8 T cells are dispensable for experimental autoimmune prostatitis induction and chronic pelvic pain development.

Introduction: Chronic Pelvic Pain Syndrome or Chronic Prostatitis (CPPS/CP) is the most prevalent urologic affliction among young adult men. It is a challenging condition to treat, which significantly decreases patient quality of life, mostly because of its still uncertain aetiology. In that regard, an autoimmune origin is a prominent supported theory. Indeed, studies in patients and in rodent models of Experimental Autoimmune Prostatitis (EAP) have provided compelling evidence suggesting a key role of CD4 Th1 cells in disease pathogenesis. However, the implication of other prominent effectors of the immune system, such as CD8 T cells, has yet to be studied. Methods: We herein analyzed the induction of prostatitis and the development of chronic pelvic pain in EAP using CD8 T cell-deficient animals. Results: We found similarly elevated PA-specific immune responses, with high frequencies of specific IFNg+CD4+ and IL17+CD4+ T cells in prostate draining lymph nodes from PA-immunized either CD8 KO or wild type animals with respect to controls. Moreover, these peripheral immune responses were paralleled by the development of significant chronic pelvic pain, and accompanied by prostate histological lesions, characterized by hemorrhage, epithelial cell desquamation, marked periglandular leukocyte infiltration, and increased collagen deposition in both, PA-immunized CD8 KO and wild type animals. As expected, control animals did not develop prostate histological lesions. Discussion: Our results indicate that CD8 T cells do not play a major role in EAP pathogenesis and chronic pelvic pain development. Moreover, our results corroborate the previous notion that a CD4 Th1 associated immune response drives the induction of prostate tissue inflammation and the development of chronic pelvic pain.

Patients with chronic prostatitis/chronic pelvic pain syndrome show T helper type 1 (Th1) and Th17 self-reactive immune responses specific to prostate and seminal antigens and diminished semen quality.

OBJECTIVES: To assess the presence of self-reactive immune responses to seminal and prostate antigens (PAg), biomarkers of inflammation of the male genital tract, and semen quality parameters in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). PATIENTS, SUBJECTS AND METHODS: Peripheral blood and semen samples were collected from patients with CP/CPPS and age-matched healthy control volunteers. We analysed the lymphoproliferative responses of peripheral blood mononuclear cells (PBMC) to different seminal plasma (SP)-derived and purified PAg, serum autoantibodies specific to PAg, leucocyte subpopulations, and inflammatory cytokines in semen, sperm apoptosis/necrosis, and semen quality parameters. RESULTS: Significantly greater PBMC proliferative responses specific to PAg, with elevated secretion of interferon (IFN)γ and interleukin (IL)-17, were detected in the patients with CP/CPPS vs the controls. Moreover, the patients with CP/CPPS had significantly greater serum immunoglobulin G immune reactivity to SP proteins, such as prostate-specific antigen and prostatic acid phosphatase, than the controls. Inflammation of the male genital tract was exemplified by high levels of IFNγ, IL-17, IL-1ß and IL-8, as well as higher counts of leukocytes, mainly CD4 T lymphocytes and macrophages, in the semen. In addition, this local inflammation was associated with an overall diminished semen quality, i.e., reduced sperm concentration, motility and viability; and higher levels of sperm apoptosis/necrosis in patients with CP/CPPS vs controls. CONCLUSION: Patients with CP/CPPS show T helper type 1 (Th1) and Th17 immune responses specific to PAg associated with chronic inflammation of the male genital tract and reduced semen quality. These immune responses may underlie the induction and development of chronic pelvic pain and inflammation of the male genital tract, which in turn could alter normal prostate functioning and impair semen quality.

Brazilian berry extract (Myrciaria jaboticaba): A promising therapy to minimize prostatic inflammation and oxidative stress.

BACKGROUND: Brazilian berry is a fruit popularly known as "Jaboticaba," rich in bioactive compounds with antioxidant and anti-inflammatory properties. Senescence and overweight are increasing worldwide and are considered risk factors to prostatic pathogenesis mainly due to oxidative and inflammatory processes induction. Thus, this study aimed to evaluate the effect of two increasing doses of the patented jaboticaba peel extract (PJE) on oxidative-stress and inflammation in the prostate of aging or high-fat-fed aging mice. METHODS: PJE and/or high-fat diet (HFD) treatments started with 11-month-old mice and lasted 60 days. The levels or the immunoexpression of different inflammatory (nuclear factor κB [NFκB], CD3+, cyclooxygenase 2 [COX-2], toll-like receptor 4 [TLR4], phosphorylated signal transducers and activators of transcription 3 [pSTAT-3], tumor necrosis factor α [TNF-α], interleukin 6 [IL-6], and IL-1ß) and oxidative-stress (catalase, superoxide dismutase 2 [SOD2], glutathione reductase [GSR], reduced glutathione, and glutathione peroxidase 3 [GPx3]) related molecules were analyzed by western-blotting, immunohistochemistry, and enzyme-linked immunosorbent assays. RESULTS: Both PJE doses reduced the levels of oxidative-stress-related molecules (GPx3, GSR, catalase), lipid peroxidation (4-hydroxynonenal), inflammatory mediators (COX-2, TNF-α, and pSTAT-3) and CD3+ T cells number, which were associated with the maintenance of the glandular morphological integrity in aging and HFD-fed-aging mice. Nevertheless, only the high PJE dose reduced the NFκB and TLR4 levels in aging mice; and SOD2, IL-6, and IL-1ß levels in HFD-aging mice. Aging itself promoted an oxidative inflammation in the prostate, interfering in the levels of the different oxidative-stress, lipid peroxidation, and inflammatory mediators evaluated, in association with high incidence of prostate epithelial and stromal damages. The HFD intake intensified aging alterations, showing an unfavorable prostatic microenvironment prone to oxidative and inflammatory damages. CONCLUSIONS: PJE exerted a dose-dependent effect controlling inflammation and oxidative-stress in aging and HFD-fed aging mice prostate. This fact contributed to prostate microenvironment balance recovery, preserving the tissue architecture of this gland. Thus, the PJE emerges as a potential therapy to prevent inflammation and oxidative stress in the prostate.

Implications of prostate inflammation on male fertility.

The prostate is the seat of three major causes of morbidity: benign prostatic hyperplasia, prostate cancer and prostatitis, three conditions in which inflammation has been implicated. A state of inflammation of the prostate gland, originally incited by an infection, an autoimmune response, a neurogenic stimulus or another trigger may have consequences on prostate functionality. In fact, male fertility depends intrinsically on the content of prostatic fluid factors secreted by the prostatic epithelium. Taking into account that the prostate gland is the major male accessory gland that exerts essential functions for male fertility, a state of local inflammation can alter male fertility by either directly impairing sperm quality or, indirectly, by causing prostate dysfunction. In the present review, we summarise the current knowledge regarding prostatitis due to well-known infections such as Escherichia coli, Chlamydia trachomatis and other commonly identified microorganisms focusing on inflammatory markers detected during these infections and seminal quality and male fertility alterations reported. We also focused on type III prostatitis or chronic nonbacterial prostatitis/chronic pelvic pain syndrome, of unknown aetiology, in which inflammation of an autoimmune origin, neurogenic stimuli or another trigger have been proposed and fertility alterations reported.

Inefficient N2-Like Neutrophils Are Promoted by Androgens During Infection.

Neutrophils are major effectors of acute inflammation against infection and tissue damage, with ability to adapt their phenotype according to the microenvironment. Although sex hormones regulate adaptive immune cells, which explains sex differences in immunity and infection, little information is available about the effects of androgens on neutrophils. We therefore aimed to examine neutrophil recruitment and plasticity in androgen-dependent and -independent sites under androgen manipulation. By using a bacterial model of prostate inflammation, we showed that neutrophil recruitment was higher in testosterone-treated rats, with neutrophil accumulation being positively correlated to serum levels of testosterone and associated to stronger inflammatory signs and tissue damage. Testosterone also promoted LPS-induced neutrophil recruitment to the prostate, peritoneum, and liver sinusoids, as revealed by histopathology, flow cytometry, and intravital microscopy. Strikingly, neutrophils in presence of testosterone exhibited an impaired bactericidal ability and a reduced myeloperoxidase activity. This inefficient cellular profile was accompanied by high expression of the anti-inflammatory cytokines IL10 and TGFß1, which is compatible with the "N2-like" neutrophil phenotype previously reported in the tumor microenvironment. These data reveal an intriguing role for testosterone promoting inefficient, anti-inflammatory neutrophils that prolong bacterial inflammation, generating a pathogenic environment for several conditions. However, these immunomodulatory properties might be beneficially exploited in autoimmune and other non-bacterial diseases.

Chronic Pelvic Pain Development and Prostate Inflammation in Strains of Mice With Different Susceptibility to Experimental Autoimmune Prostatitis.

BACKGROUND: Experimental autoimmune prostatitis (EAP) is an autoimmune inflammatory disease of the prostate characterized by peripheral prostate-specific autoimmune responses associated with prostate inflammation. EAP is induced in rodents upon immunization with prostate antigens (PAg) plus adjuvants and shares important clinical and immunological features with the human disease chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: EAP was induced in young NOD, C57BL/6, and BALB/c male mice by immunization with PAg plus complete Freund́s adjuvant. Tactile allodynia was assessed using Von Frey fibers as a measure of pelvic pain at baseline and at different time points after immunization. Using conventional histology, immunohistochemistry, FACS analysis, and protein arrays, an interstrain comparative study of prostate cell infiltration and inflammation was performed. RESULTS: Chronic pelvic pain development was similar between immunized NOD and C57BL/6 mice, although the severity of leukocyte infiltration was greater in the first case. Coversely, minimal prostate cell infiltration was observed in immunized BALB/c mice, who showed no pelvic pain development. Increased numbers of mast cells, mostly degranulated, were detected in prostate samples from NOD and C57BL/6 mice, while lower total counts and resting were observed in BALB/c mice. Prostate tissue from NOD mice revealed markedly increased expression levels of inflammatory cytokines, chemokines, adhesion molecules, vascular endothelial growth factor, and metalloproteinases. Similar results, but to a lesser extent, were observed when analyzing prostate tissue from C57BL/6 mice. On the contrary, the expression of the above mediators was very low in prostate tissue from immunized BALB/c mice, showing significantly slight increments only for CXCL1 and IL4. CONCLUSIONS: Our results provide new evidence indicating that NOD, C57BL/6, and BALB/c mice develop different degrees of chronic pelvic pain, type, and amount of prostate cell infiltration and secretion of inflammatory mediators. Our results corroborate and support the notion that mice with different genetic background have different susceptibility to EAP induction. Prostate 77:94-104, 2017. © 2016 Wiley Periodicals, Inc.

Regulatory T cells control strain specific resistance to Experimental Autoimmune Prostatitis.

Susceptibility to autoimmune diseases results from the encounter of a complex and long evolved genetic context with a no less complex and changing environment. Major actors in maintaining health are regulatory T cells (Treg) that primarily dampen a large subset of autoreactive lymphocytes escaping thymic negative selection. Here, we directly asked whether Treg participate in defining susceptibility and resistance to Experimental Autoimmune Prostatitis (EAP). We analyzed three common laboratory strains of mice presenting with different susceptibility to autoimmune prostatitis upon immunization with prostate proteins. The NOD, the C57BL/6 and the BALB/c mice that can be classified along a disease score ranging from severe, mild and to undetectable, respectively. Upon mild and transient depletion of Treg at the induction phase of EAP, each model showed an increment along this score, most remarkably with the BALB/c mice switching from a resistant to a susceptible phenotype. We further show that disease associates with the upregulation of CXCR3 expression on effector T cells, a process requiring IFNγ. Together with recent advances on environmental factors affecting Treg, these findings provide a likely cellular and molecular explanation to the recent rise in autoimmune diseases incidence.

Expression of CXCR3 on specific T cells is essential for homing to the prostate gland in an experimental model of chronic prostatitis/chronic pelvic pain syndrome.

Experimental autoimmune prostatitis (EAP) is considered a valid model for the human disease chronic prostatitis/chronic pelvic pain syndrome. In this report, we analyzed phenotypic characteristics of T cells that gain access to the prostate and induce leukocyte recruitment in mice with different susceptibility to EAP. After EAP induction, NOD mice developed a specific cellular response characterized by a mixed Th1/Th17 pattern with specific T cells mainly expressing CXCR3 that infiltrated and damaged the prostate. In contrast, BALB/c mice, as well as NOD-IFN-γ(-/-), exhibited only Th17 cells mainly expressing CCR6 that were not capable of infiltrating the prostate gland. Adoptive transfer experiments of T cells from NOD or NOD-IFN-γ(-/-) mice to NOD-SCID recipients showed that only T cells from NOD mice successfully infiltrated the prostate. However, after "in vitro" or "in vivo" treatment with rIFN-γ, T cells from NOD-IFN-γ(-/-) mice became capable of homing to the prostate and induced leukocyte recruitment. Chemokine levels in prostate tissue from NOD mice showed increased expression levels of CXCR3 ligands. Additional experiments using adoptive transfer of sorted CXCR3(+)CD3(+) T cells or administrating a CXCR3 antagonist treatment confirmed these previous results. Altogether, our results demonstrate that the expression of CXCR3 on effector T cells is essential for their homing to the prostate gland in EAP. CXCR3 emerges as a potential therapeutic target to control chronic prostatitis/chronic pelvic pain syndrome.

Acute inflammation promotes early cellular stimulation of the epithelial and stromal compartments of the rat prostate.

BACKGROUND: It has been proposed that prostatic inflammation plays a pivotal role in the pathophysiology of benign hyperplasia and prostate cancer. However, little information is available about the prostatic reaction to bacterial compounds in vivo. Our aim was therefore to evaluate the early effects of bacterial infection on rat ventral prostate compartments. METHODS: Using a rat model of acute bacterial prostatitis by Escherichia coli, we analyzed the histological and ultrastructural changes in the prostate at 24, 48, and 72 hr postinfection. Prostatic tissues were immunostained for prostatic binding protein (PBP), ACTA2, ErbB1, and ErbB2 receptors, TUNEL, and markers of cell proliferation. Dot and Western blots for PBP, ACTA2, ErbB1, ErbB2, and TGFbeta1 were also performed. RESULTS: The prostatic epithelium became hypertrophied, with increases in PBP and ErbB1 expression at 24 hr postinfection. Moreover, inflammation induced the expression of ErbB2, a receptor strongly involved in carcinogenesis. These alterations were more pronounced at 48 hr, but the epithelium also showed apoptosis and finally atrophy at 72 hr postinfection, with a decrease in PBP and ErbB receptors. Interestingly, the epithelial cells exhibited a high level of proliferation in response to the bacteria. The stromal reaction to acute inflammation was initially characterized by smooth muscle hypertrophy. Afterwards, muscle cells acquired a secretory phenotype, with a reduction in ACTA2 at 72 hr postinfection. CONCLUSIONS: Prostatic inflammation, even at the early stages, promotes atrophic and proliferative changes, and the upregulation of ErbB receptors together with dedifferentiation of smooth muscle cells. These data suggest that repetitive reinfections could lead to uncontrolled growth in the prostate gland.

Crucial role of interferon-gamma in experimental autoimmune prostatitis.

PURPOSE: An autoimmune etiology is proposed in some patients with chronic nonbacterial prostatitis since they show interferon-gamma secreting lymphocytes specific to prostate antigens in the periphery and increased interferon-gamma in seminal plasma. We investigated the involvement of interferon-gamma in an animal model of autoimmune prostatitis. MATERIALS AND METHODS: Experimental autoimmune prostatitis was studied in the no-obese diabetic and C57Bl/6 (Harlan, Zeist, The Netherlands) susceptible mouse strains, and in the IRF-1 KO and STAT-1 KO mouse strains deficient in transcription factors involved in interferon-gamma signaling. RESULTS: Experimental autoimmune prostatitis was characterized by prostate specific interferon-gamma secreting cells in the periphery and by T-helper 1 related cytokines in the target organ. Increased interferon-gamma and interleukin-12 were observed in the prostate of autoimmune animals while interleukin-10 and interleukin-4 were decreased and unaltered, respectively. The absence of transcription factors involved in the interferon-gamma signaling cascade, IRF-1 and STAT-1, made mice resistant to experimental autoimmune prostatitis. IRF-1 KO and STAT-1 KO mice immunized with prostate antigens did not show infiltration or alterations in the prostate. They did not have the typical prostate specific autoimmune response and showed decreased interferon-gamma, interleukin-12 and interleukin-10, and augmented interleukin-4 in the prostate. CONCLUSIONS: Our results argue for a crucial role of interferon-gamma as a key factor in the pathogenesis of the disease. Intense research is promptly required to identify the pathogenic mechanisms underlying chronic prostatitis/chronic pelvic pain syndrome to find a more rational therapy.

Expression of Toll-like receptor 4 in the prostate gland and its association with the severity of prostate cancer.

BACKGROUND: Chronic inflammation has been postulated to be an important driving force to prostate carcinoma. Toll-like receptors (TLRs) compose a family of receptors mainly expressed on immune cells. Recently, functional TLRs have been shown to be also expressed in numerous cancer cells, but their significance has only recently begun to be explored. The purpose of this study was to investigate the putative role of TLR4 expression in prostate carcinoma. METHODS: To determine if there is an association between TLR4 expression and the malignancy of the tumor, 35 prostate carcinoma samples showing different Gleason grades were analyzed by immunohistochemistry. Also, to explore the functionality of the receptors expressed on the epithelium, we analyzed the type of cytokine response elicited and the signaling pathways involved after TLR4 triggering in the human prostate adenocarcinoma cell line, DU-145. RESULTS: TLR4 is expressed in the normal prostate gland in both stroma and epithelium. TLR4 expression significantly drops to negative values as the Gleason grade augments in both, stroma and epithelium. Moreover, DU-145 cells also exhibit TLR4 expression and respond to TLR4 agonists, activating the transcription factor NF-kappaB and increasing the expression of pro-inflammatory mediators. Inhibition of the molecular adaptors MyD88 and MAL by overexpression of dominant-negative mutants diminished LPS-induced activation of NF-kappaB, showing that DU-145 cells activate the NF-kappaB through MyD88-dependent signaling pathways. CONCLUSIONS: We hypothesize that TLR4 in prostate cells could synergize with innate immune cells contributing to an eventual inflammatory process, which in genetically prone individuals could promote carcinogenesis. Prostate 69: 1387-1397, 2009. (c) 2009 Wiley-Liss, Inc.

Impact of vitamin D receptor activity on experimental autoimmune prostatitis.

Chronic non bacterial prostatitis is a chronic inflammatory syndrome. Its etiology and physiopathology are unclear and treatments are empirical and ineffective in most cases. Autoimmunity has been proposed as an etiology. In the present report, we investigated the impact of vitamin D receptor silencing, by use of VDR-KO NOD mice and the immune-modulating effect of the vitamin D3 analog TX527 on the development of Experimental Autoimmune Prostatitis in NOD mice. VDR-KO NOD mice developed a more aggressive form of autoimmune prostatitis characterized by a greater lymphoproliferative response against prostate antigen in vitro (6.92+/-4.77 vs. 2.47+/-0.41 21 days after disease induction, p<0.05) and higher levels of specific INFgamma secretion (471+/-6 vs. 386+/-5pg/ml, p<0.01). This was accompanied in vivo by more severe lesions and augmented mononuclear cell infiltration in the prostate gland. On the other hand, although analog-treated mice showed a significant reduction in the spleen T-cell specific proliferative response against prostate antigen in vitro, no effect on disease development was observed. We conclude that vitamin D receptor modulation holds the promise of interfering with autoimmune prostatitis. Introduction of more powerful analogs, or combinations with anti-T-cell reagents may represent therapeutic solutions for these group of patients.

Effects of autoimmunity to the prostate on the fertility of the male rat.

OBJECTIVE: To study the putative direct consequences of autoimmunity to the prostate on male semen quality and fertility potential. DESIGN: Experimental animal study. SETTING: Immunology, CIBICI-CONICET, National University of Cordoba, Argentina. ANIMAL(S): Twelve male and 24 female Wistar rats. INTERVENTION(S): Autoimmune prostatitis was induced following a standard protocol. MAIN OUTCOME MEASURE(S): Citric acid, zinc, sperm vitality, reactive oxygen species levels, total antioxidant capacity, DNA fragmentation, and lipid peroxidation were analyzed in semen samples. Mating studies were also performed, and different fertility parameters (potency, fecundity index, fertility index, fetus size, and preimplantation and postimplantation embryo loss) were assayed. RESULT(S): Citric acid and zinc levels were decreased in seminal samples from autoimmune rats. Increased reactive oxygen species values and lower levels of total antioxidant capacity were shown in semen samples from autoimmune animals. Moreover, decreased levels of sperm vitality, high percentages of damaged DNA sperm cells, and elevated lipid peroxidation levels also were shown in semen from autoimmune rats. A significant decrease in the fertility index and augmented percentages of embryo loss were observed in the autoimmune group. CONCLUSION(S): An autoimmune response to the prostate impairs its functionality and induces important alterations in seminal oxidative balance, producing higher levels of lipid peroxidation and sperm DNA damage. Moreover, autoimmunity to the prostate gland seriously compromises male fertility.

Autoimmune prostatitis: state of the art.

The prostate is one of the main male sex accessory glands and the target of many pathological conditions affecting men of all ages. Pathological conditions of the prostate gland range from infections, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) of a still unknown aetiology to benign hyperplasia and cancer. CP/CPPS is one of the most prevalent diseases in the urologic clinic and affects men younger than 50 years old. A significant advance in the understanding of CP/CPPS was made when an autoimmune response against prostate antigens was revealed in a considerable number of patients. During the last 30 years, extensive work has been done regarding the development and characterization of different rodent models of experimental autoimmune prostatitis (EAP). It has been demonstrated that tolerance to prostate antigens can be disrupted in some strains of rats and mice and cellular and humoral responses to prostate antigens are elicited. A Th1 pattern has been described and the cellular response seems to be the major pathogenic mechanism involved. Immune cells infiltrate the gland and induce prostate lesions. The genetic background and hormonal imbalance are factors that could contribute to the onset of the disease in susceptible young males. Moreover, spontaneous autoimmune prostatitis could also occur with advanced age in susceptible strains. In this review, we summarize the current knowledge regarding rodent models of EAP and the immunological alterations present in CP/CPPS patients. We also discuss the reliability of these experimental approaches as genuine tools for the study of human disease.

Autoimmune etiology in chronic prostatitis syndrome: an advance in the understanding of this pathology.

The prostate is the target of many inflammatory and neoplastic disorders that affect men of all ages. Pathological conditions of the prostate gland range from infection of this organ by ascending bacteria from infected urine, to chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) of a still unknown etiology (accompanied with inflammation and lymphocyte infiltration of the gland), to benign hyperplasia and cancer. Patients under 50 years of age usually suffer from CP/CPPS, a chronic inflammatory syndrome characterized by pelvic pain, irritative voiding symptoms, and sexual dysfunction complaints. In this review, we summarize the current knowledge regarding immunological alterations present in CP/ CPPS patients. Remarkably, an inflammation state, in the absence of an invading infectious agent, is established in these patients, suggesting that an autoimmune process could be involved. In fact, specific autoimmune response to prostate antigens has recently been reported in CP/CPPS patients. Autoimmune response to prostate gland affects the seminal quality reported in these patients and may have critical consequences in their fertility. It is anticipated that preclinical studies in experimental models for CP/CPSS will provide important insights into the etiopathogenic mechanisms involved in this disease. We discuss here the similarities and the differences between human disease and experimental models and argue for the importance of the prostate gland in male reproductive function. Ultimately, we suggest that a state of inflammation, originally incited by an autoimmune response within the prostate, together with a diminished prostate functionality, may compromise male fertility.

Prostate epithelial cells can act as early sensors of infection by up-regulating TLR4 expression and proinflammatory mediators upon LPS stimulation.

Despite the prevalence of prostate disease, little is known about the immunobiology of the prostate and its contribution to disease. The main goal of this work was to investigate how prostate epithelial cells deal with inflammatory stimuli. To this aim, we stimulated a rat prostate epithelial cell line [metastasis-lung (MAT-LU)] or rat primary epithelial cells with lipopolysaccharide (LPS). Prostate epithelial cells constitutively express significant levels of Toll-like receptor 4 (TLR4) and CD14 mRNA. TLR2 transcription could also be demonstrated, suggesting that these cells could recognize a broader spectrum of microbial molecular patterns. TLR4, TLR2, and CD14 proteins were also detected, although not at the cell surface but intracellularly. Prostate epithelial cells not only express these receptors, but they are also able to respond to LPS, and LPS-stimulated MAT-LU cells activate nuclear factor-kappaB transcription factor, induce the expression of inducible nitric oxide (NO) synthase, and secrete NO. Even more, numerous chemokine genes are up-regulated or induced in this response. Our results clearly demonstrate that prostate epithelial cells are fully competent to respond. The fact that they express TLR4 and TLR2 intracellularly suggests the presence of regulatory mechanisms, which once overcome, could turn these cells into active players of the innate immunity, capable of initiating an inflammatory response.

Presence of INFgamma-secreting lymphocytes specific to prostate antigens in a group of chronic prostatitis patients.

Acute and chronic infectious prostatitis are the best understood of the prostate syndromes, but they are the least frequent. In contrast, although chronic non-infectious prostatitis is the most frequent syndrome, its cause has proved elusive despite years of investigation. In the present study, we analyzed a group of patients with infectious and non-infectious chronic prostatitis in order to search for the presence of a possible autoimmune response to prostate antigens. We demonstrated the presence of lymphocytes able to proliferate in response to known human prostate antigens such as PSA and PAP only in a group of patients with non-infectious chronic prostatitis. We observed that, as in other autoimmune diseases, a proliferative response against two or more autoantigens was a common feature. Moreover, when INFgamma and IL-10 levels were measured in culture supernatants, significantly elevated levels of INFgamma were detected only in samples from patients with positive proliferative response to prostate antigens. Interestingly, only these patients showed significantly elevated levels of inflammatory cytokines (IL-1 and TNF-alpha) in seminal plasma, arguing for a local inflammation of non-infectious cause. Our results show that INFgamma-secreting lymphocytes specific to prostate antigens are in fact detected in 34% of the patients with chronic non-infectious prostatitis. We speculate that these cells could be involved in the inflammatory process taking place in the prostate gland and therefore could alter its biological function.

Reduced semen quality in chronic prostatitis patients that have cellular autoimmune response to prostate antigens.

BACKGROUND: The relationship between chronic prostatitis and fertility has been controversial for many years. We have previously shown the presence of a cellular autoimmune response against prostate antigens in a group of chronic prostatitis patients. Our main goal was to investigate whether chronic prostatitis (either caused by an infection or an autoimmune response to the prostate gland) could have a deleterious effect on semen quality. METHODS: Forty-four patients diagnosed as suffering from chronic prostatitis were included and divided into groups according to the presence of infection and/or cellular autoimmune response against prostate antigens. Healthy normal individuals were included as controls. Measurements for sperm concentration, motility, morphology, prostate and seminal vesicle markers, antisperm antibodies, white blood cells and pro-inflammatory cytokines were performed accordingly. RESULTS: The most severe abnormalities were seen in patients with no evident infection and an autoimmune response against prostate antigens. Moreover, significantly increased levels of pro-inflammatory cytokines were detected in seminal plasma from these patients. CONCLUSIONS: This study shows that chronic prostatitis patients with cellular autoimmune response to prostate antigens present important alterations in their semen quality parameters. We speculate that an autoimmune response against prostate antigens and the inflammatory process involved may affect male fertility.

Experimental autoimmune prostatitis: dihydrotestosterone influence over the immune response.

PURPOSE: In experimental autoimmune prostatitis in a rat model of chronic prostatic inflammation of noninfectious origin the prostatic 5alpha-dihydrotestosterone (DHT) concentration decreases because of depressed 5alpha-reductase activity. This decrease in androgens in situ could favor the development of autoimmune status at the same time. We noted that a DHT increase could protect the gland from immune aggression and/or its consequences in regard to prostatic androgenic metabolism. MATERIALS AND METHODS: We analyzed in vitro the (3H)-DHT enzymatic bioconversion of prostate homogenates of male accessory sexual gland extract (MAG) immunized rats and MAG immunized plus DHT implanted rats (DSG rats), and performed ventral prostate histological observations. The specific cell immune response against MAG antigen(s) was studied by delayed type hypersensitivity. RESULTS: In DSG and MAG rats, and controls enzymatic activities (3alpha/3beta-hydroxysteroid oxidoreductases) were 112.7 +/- 11.3, 91.4 +/- 15.0 (not significant) and 147.0 +/- 12.8 pmol per minute per mg protein (p <0.025). Histological findings in DSG rat ventral prostates revealed infiltrating mononuclear cell foci in lower quantity and less magnitude than in MAG rat prostates. Delayed type hypersensitivity values were positive in MAG rats and lower in DSG rats in relation to kidney treated and untreated rats. CONCLUSIONS: Results suggest that constantly elevated DHT levels could decrease the cell immune response but not at significantly. In contrast, androgenic metabolism remains altered in the presence of exogenous androgens.