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The aim of the present work was to study the immune profiling of prostate epithelial cells by the expression of ASK-1/p38 and Raf-1/ERK MAP Kinases signaling pathways mediated by TRAF-6. Immunohistochemical and Western blot analyses for TRAF-6, ASK-1, MEK-6, p38, Raf-1, MEK-1, ERK-1, ERK-2 and PSA were carried out in 5 samples of normal prostate gland, 24 samples of BPH and 19 samples of PC. Immunoreaction to TRAF-6 was found in the cytoplasm of epithelial cells of BPH and tumor cells of PC samples. For patients with the profile (TRAF-6+), optical densities revealed a weak immunoexpression of ASK-1 in PC compared to BPH patients. Whereas, immunoexpression to Raf-1 was higher in PC than in BPH. According to the expression of ASK-1 and Raf-1, two main profiles were identified: (TRAF-6+, ASK-1+, Raf-1+) and (TRAF-6+, ASK-1+, RAF-1-) in both BPH and PC. In addition, ASK-1/p38 axis expression was increased in BPH. Raf-1/ERK signaling pathway was increased in PC samples. On the other hand, representing of individual signaling protein expression enclosing each of p38 and ERK MAP Kinases according to TRAF-6+ showed a qualitative behavior of ASK61/p38 and Raf-1/ERK signaling pathways and a dynamic expression of PSA associated with immune and inflammatory process. These findings suggest that prostate epithelial cell could able an immune and inflammatory setting., (Copyright © 2017. Published by Elsevier Taiwan.)

Background: In this study was investigate IAPs in normal human prostate (NP), benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostatic carcinoma (PC), and their involvement in apoptosis/proliferation via NF-kB (TNF-alpha, IL-1) stimulation., Methods: Immunohistochemical and Western blot analyses were performed in 10 samples of normal prostates, 35 samples of BPH, 27 samples diagnosis of PIN (with low-grade PIN or high-grade PIN) and 95 samples of PC (with low, medium or high Gleason grades)., Results: In NP, cytoplasm of epithelial cells were positive to c-IAP1/2 (80% of samples), c-IAP-2 (60%), ILP (20%), XIAP (20%); negative to NAIP and survivin. In BPH, epithelial cells were immunostained to c-IAP1/2 (57.57%), c-IAP-2 (57.57%), ILP (66.6%), NAIP (60.6%), XIAP (27.27%), survivin (9.1%). Whereas low-grade PIN showed intermediate results between NP and BPH; results in high-grade PIN were similar to those found in PC. In PC, epithelial cells were immunostained to c-IAP1/2, c-IAP-2, ILP, NAIP, XIAP (no Gleason variation) and survivin (increasing with Gleason)., Conclusions: IAPs could be involved in prostate disorder (BPH, PIN and PC) development since might be provoke inhibition of apoptosis and subsequently cell proliferation. At the same time, different transduction pathway such as IL-1/NIK/NF-kB or TNF/NF-kB (NIK or p38) also promotes proliferation. Inhibitions of IAPs, IL-1alpha and TNFalpha might be a possible target for PC treatment since IAPs are the proteins that inhibited apoptosis (favour proliferation) and IL-1alpha and TNFalpha would affect all the transduction pathway involucrate in the activation of transcription factors related to survival or proliferation (NF-kB, Elk-1 or ATF-2).

Background: The aim of this study was to relate the expression, analyzed by Western blot and immunohistochemistry, of several pro-inflammatory cytokines, including IL-1, IL-6 and TNF-alpha, with serum levels of prostate-specific antigen (PSA) in normal and pathologic (hyperplasia and cancer) prostate tissues to elucidate their possible role in tumor progression. We are also discussing the possible use of these cytokines as a potential therapeutic target., Methods: The study was carried out in 5 normal, 25 benign prostatic hyperplastic (BPH) and 17 cancerous human prostates (PC). Immunohistochemical and Western blot analysis were performed. Serum levels of PSA were assayed by an immulite autoanalyzer., Results: The most relevant results showed that in BPH, IL-1alpha, IL-6 and tumor necrosis factor (TNF) were only expressed in patients with PSA serum levels of 0-4 or 4-20 ng/ml, but not in the group >20 ng/ml. In PC these cytokines were only expressed in patients with PSA serum levels >4 ng/ml., Conclusions: In PC there was an association between the high expression of pro-inflammatory cytokines (TNFalpha, IL-6, IL-1), elevated serum levels of PSA and cancer progression. A better understanding of the biologic mechanism of this association may provide new targets for therapy in these patients.

Background: The principal components of the interleukin-1 (IL-1) family are two secreted factors (IL-1alpha and IL-1beta), two transmembrane receptors (IL-1RI [biologically active] and IL-1RII [inert receptor]), and a natural antagonist receptor of IL-1 function (IL-1Ra). Changes in the expression pattern of these IL-1 members have been reported to be related to disease progression. The objective of the current study was to evaluate these changes in prostatic tissue by means of immunohistochemistry and Western blot analysis., Methods: Immunohistochemical and Western blot analyses were performed in 20 normal samples, 35 samples of benign prostatic hyperplasia (BPH) and 27 samples from patients with prostate carcinoma (PC)., Results: In normal prostate samples, immunoreactions to IL-1beta and IL-1RI were positive, whereas there were no immunoreactions observed to IL-1alpha, IL-1RII, or IL-1Ra. In BPH, in addition to immunoreactions to IL-1beta and IL-1RI, immunoreactions to IL-1alpha, IL-1RII, and IL-1Ra were observed in many samples. In samples of PC with low Gleason grade, most tumors had positive immunoreactions to IL-1alpha and IL-1RI. In samples of PC with high Gleason grade, immunoreactions were seen only to IL-1alpha, IL-1RI, and IL-1RII., Conclusions: The current results suggested that high expression levels of IL-1alpha and IL1-RI in epithelial cells in BPH and PC samples were involved in cell proliferation and that the loss of immunoexpression of IL-1beta and IL-1Ra was a characteristic feature of PC compared with normal prostate samples and BPH. Because this loss is progressive up to a complete absence of immunoexpression in PC of high Gleason grade, the evaluation of IL-1beta and IL-1Ra in PC may be significant in assessing for malignancy., (Copyright 2004 American Cancer Society.)

Interleukin-6 (IL-6) and its receptor have been implicated in prostate cancer progression. Because other members of the IL-6 family such as leukaemia inhibitory factor (LIF) and oncostatin M (OSM) share gp130, the signal transduction subunit of their receptors, interpretation of the data without considering the expression of these cytokines and their specific receptor subunits could be misleading. The immunohistochemical pattern of the IL-6 family and their receptor subunits in normal prostate, benign prostatic hyperplasia (BPH), and prostatic carcinoma (PC) was investigated. In normal prostates, gp130 and OSMRalpha were detected exclusively in the stroma and LIFRbeta was very scarce. While IL-6 was scarcely immunolocalized to the basal cells of the epithelium, OSM was detected in the stroma and LIF in both the epithelium and the stroma. This suggests an autocrine role for this family of cytokines in the stroma of normal prostates. In BPH, gp130 and OSMRalpha were detected both in the epithelium and in the stroma, whereas LIFRbeta was localized only to the epithelium. IL-6 localized preferentially to the epithelium, OSM to the stroma, and LIF to both compartments. Therefore, in addition to the autocrine role in the stroma, IL-6 and OSM may play a paracrine role from the stroma to the epithelium in BPH. In PC, gp130 and OSMRalpha were detected both in the epithelium and in the stroma, increasing with rising Gleason grade, whereas LIFRbeta was localized exclusively to the epithelium of low Gleason grade carcinomas. IL-6, LIF, and OSM localized in all cell types, with immunostaining increasing with Gleason grade. These data suggest an autocrine role for these cytokines in the epithelial cells of PC. The distinct pattern of expression of LIFRbeta exclusively in low Gleason grade carcinomas makes LIFRbeta a candidate for malignancy diagnosis. The role of OSM mainly in high Gleason grade carcinomas makes OSM a putative target for prostate cancer therapy., (Copyright 2003 John Wiley & Sons, Ltd.)

Purpose: Tumor necrosis factor-alpha (TNF-alpha) exerts apoptosis throughout an intracellular transduction pathway that involves the protein kinases TRAF-2 (integration point of apoptotic and survival signals), signal regulating kinase (ASK-1) (pro-apoptotic protein), mitogen activated protein kinase-kinase 4 (MEK-4) (p38 activator and metastasis suppressor gene), Jun N-terminal kinase (JNK) (stress mitogen activated protein kinase) and the transcription factor activator protein-1 (AP-1)., Materials and Methods: Biopsies from 20 normal, 35 hyperplastic and 27 carcinomatous human prostates were obtained for immunohistochemical and Western blot studies of the mentioned TNF-alpha/AP-1 transduction pathway members., Results: In normal prostates immunoreactions to TRAF-2, ASK-1, MEK-4 and JNK were positive, while no immunoreaction to AP-1 was detected. Although in benign prostatic hyperplasia the percent of immunostained specimens and intensity of immunoreactions to TRAF-2, ASK-1, MEK-4 and JNK decreased, the immunoreaction to AP-1 was positive in 27.3%. In most carcinomatous specimens the immune reaction was negative for all proteins of the TRAF-2/AP-1 pathway., Conclusions: The TNF-alpha/AP-1 pathway might be a response to the excessive proliferative stimulus, although this response seems to be insufficient to counteract extracellular signals of cell proliferation. In prostate cancer this pathway is probably inactivated by other factors, such as p21 (at the ASK-1 level) or bcl-2 (at the JNK level).

This study investigate the expression of the mitogen-activated protein kinases (MAPKs) in normal prostate, benign prostatic hyperplasia (BPH), and prostatic cancer (PC), and also the possible relationship between the activity of these MAPKs and the apoptosis/proliferation index. Immunochemical techniques were carried out using 2 mouse monoclonal antibodies against human extracellular signal-regulated protein kinase (ERK) and Jun N-terminal kinase (JNK), and 1 goat polyclonal antibody against mouse p38. To compare the results obtained in the 3 specimens, the average percentages of both epithelial and stromal immunostained cells were calculated on immunostained sections. For each of the 3 kinases studied, the percentage of immunostained stromal cells did not change with prostatic alterations. For both ERK and p38, the percentage of immunostained epithelial cells increased significantly in BPH and even more so in PC. For JNK, the percentage of immunostained epithelial cells increased significantly only in PC. These results suggest that ERK could be involved in the elevated proliferation indexes reported in BPH and PC, whereas p38 might contribute to the increased apoptotic index reported in PC. The most probable action of JNK in PC would be cell proliferation stimulation. Overexpression of MAPKs, involved in the development of prostatic hyperplasia and neoplasia, might be secondary to the overexpression of several growth factors., (Copyright 2002, Elsevier Science (USA). All rights reserved.)