Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Androgen receptors are present at low densities in osteoblasts. Androgens are also metabolized in bone. (Non)aromatizable androgens probably induce proliferation of osteoblasts and differentiation. A direct effect of androgens on osteoclasts has not been demonstrated. Androgens may however inhibit bone resorption indirectly, by an inhibition of the recruitment of osteoclast precursors from bone marrow, by decreased secretion of interleukin-6 and/or prostaglandin E2, and/or by an increased sensitivity of marrow cells or osteoblasts for bone resorption stimulating factors such as PTH. The recent demonstration of androgen receptors in bone marrow stromal and osteoclast-like cells opens new perspectives in this respect. During puberty, androgens stimulate bone growth both directly and indirectly. Observations in androgen-resistant animals clearly demonstrated that the sexual dimorphism of bone depends on the presence of a functional androgen receptor. Optimal peak bone mass seems related to an appropriately timed androgen secretion. In adults, androgens are also involved in maintenance of the male skeleton. Androgen replacement may prevent further bone loss in hypogonadal men, however, it seems difficult to fully correct bone mass in these men.
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PMID:Androgens and bone. 762 37

Interleukin-6 is an essential mediator of the bone loss caused by loss of estrogens. Because loss of androgens also causes bone loss, we have examined whether the IL-6 gene is regulated by androgens, and whether IL-6 plays a role in the bone loss caused by androgen deficiency. Both testosterone and dihydrotestosterone inhibited IL-6 production by murine bone marrow-derived stromal cells. In addition, testosterone, dihydrotestosterone, and adrenal androgens inhibited the expression of a chloramphenicol acetyl transferase reporter plasmid driven by the human IL-6 promoter in HeLa cells cotransfected with an androgen receptor expression plasmid; however, these steroids were ineffective when the cells were cotransfected with an estrogen receptor expression plasmid. In accordance with the in vitro findings, orchidectomy in mice caused an increase in the replication of osteoclast progenitors in the bone marrow which could be prevented by androgen replacement or administration of an IL-6 neutralizing antibody. Moreover, bone histomorphometric analysis of trabecular bone revealed that, in contrast to IL-6 sufficient mice which exhibited increased osteoclast numbers and bone loss following orchidectomy, IL-6 deficient mice (generated by targeted gene disruption) did not. This evidence demonstrates that male sex steroids, acting through the androgen-specific receptor, inhibit the expression of the IL-6 gene; and that IL-6 mediates the upregulation of osteoclastogenesis and therefore the bone loss caused by androgen deficiency, as it does in estrogen deficiency.
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PMID:Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens. The role of the androgen receptor. 776 30

Androgens repress expression of many genes, yet the mechanism of this activity has remained elusive. The cytokine, interleukin-6, is active in a variety of biological systems, and its expression is repressed by androgens. Accordingly we dissected the mechanism of androgen's ability to inhibit interleukin-6 expression at the molecular level. In a series of co-transfection assays, we found that 5alpha-dihydrotestosterone, through the androgen receptor, repressed activation of the interleukin-6 promoter, in part, by inhibiting NFkappaB activity. It did not appear that 5alpha-dihydrotestosterone inhibited NFkappaB by activating the androgen receptor to compete for the NFkappaB response element as we could not detect androgen receptor binding to the IL-6 promoter by DNase I footprinting assay. However, by electrophoretic mobility shift assay we found that 5alpha-dihydrotestosterone repressed formation of NFkappaB middle dotNFkappaB response element complex formation. In LNCaP prostate carcinoma cells, 5alpha-dihydrotestosterone achieved this effect through maintenance of IkappaBalpha protein levels in the face of phorbol ester, a stimulus that results in IkappaBalpha degradation. Finally, we confirmed that IkappaBalpha inhibits NFkappaB-mediated activation of the interleukin-6 promoter. These data suggest that maintenance of IkappaBalpha levels may represent the first identified mechanism for androgen-mediated repression of a natural androgen-regulated gene.
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PMID:Inhibition of NFkappaB activity through maintenance of IkappaBalpha levels contributes to dihydrotestosterone-mediated repression of the interleukin-6 promoter. 882 77

Interleukin-6 (IL-6) levels are frequently elevated in sera of patients with metastatic prostate cancer. IL-6 receptors are expressed in prostate cancer cell lines, as well as in benign prostate hyperplasia and prostate cancer tissue specimens. The androgen receptor (AR) is a key transcription factor that is present in all stages of prostate carcinoma, even in therapy-refractory tumors. In an attempt to investigate possible cross-talk between IL-6 and androgen signal transduction cascades, we tested the effects of this cytokine on AR transcriptional activity. The regulation of AR activity by IL-6 was studied in DU-145 cells, which were cotransfected with the androgen-responsive reporter plasmid ARE2TATACAT and the AR expression vector pSG5AR. We show that IL-6 up-regulates AR activity in a ligand-independent manner, as well as synergistically, with very low doses of the synthetic androgen methyltrienolone (5-10 pM). Therefore, AR activation by IL-6 may be operative in prostate cancer patients who have decreased androgen levels because of androgen ablation therapy. The maximal induction of reporter gene activity by IL-6 alone (50 ng/ml) was 67% of that stimulated by 1 nM of methyltrienolone. The nonsteroidal antiandrogen bicalutamide (Casodex) nearly completely inhibited AR activation by IL-6. IL-6 effects on AR activity were also abolished or greatly reduced by inhibitors of protein kinase A and C and mitogen-activated protein kinase pathways. In concordance with the results obtained in DU-145 cells, IL-6 induced AR-regulated prostate-specific antigen mRNA and protein in LNCaP cells. Stimulation of prostate-specific antigen protein secretion by IL-6 was antagonized by bicalutamide and inhibitors of protein kinase A and mitogen-activated protein kinase signaling pathways. Taken together, our data show for the first time that IL-6 is a nonsteroidal activator of the AR and that this activation is implicated in the regulation of prostate-specific proteins. Keeping in mind that IL-6, its receptor, and the AR are expressed in prostate cancers, cross-talk between IL-6 and AR signaling pathways may have clinical significance.
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PMID:Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. 978 16

Androgens have beneficial effects on skeletal development and maintenance in women and men. The detection and functional characterization of androgen receptors in bone cells has implicated bone tissue as a potential target tissue for androgens. Gonadal and adrenal androgens directly regulate various aspects of osteoblastic lineage cells, including proliferation, differentiation, mineralization, and gene expression. These effects may differ depending on the stage of differentiation, the number of androgen receptors, and other inherent characteristics (species, site, cell biology) of the osteoblastic cell system. In addition, recent studies have suggested that some of the anabolic and anti-resorptive effects of androgens on bone may be mediated by regulation of autocrine and paracrine factors in the bone microenvironment, including transforming growth factor-beta, insulin-like growth factors (and their binding proteins), and interleukin-6. This review summarizes the recent progress made in our knowledge of androgen receptor action, local androgen metabolism in bone, and direct and indirect effects of gonadal and adrenal androgens as well as androgen receptor antagonists on bone cells.
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PMID:Androgen effects on bone metabolism: recent progress and controversies. 1009 44

We have investigated the role of 23 candidate genes in the control of bone mineral density (BMD) by linkage studies in families of probands with osteoporosis (lumbar spine [LS] or femoral neck [FN] BMD T score < -2.5) and low BMD relative to an age- and gender-matched cohort (Z score < -2.0). One hundred and fifteen probands (35 male, 80 female) and 499 of their first- or second-degree relatives (223 males and 276 females) were recruited for the study. BMD was measured at the LS and FN using dual-energy X-ray absorptiometry and expressed as age- and gender-matched Z scores corrected for body mass index. The candidate genes studied were the androgen receptor, type I collagen A1 (COLIA1), COLIA2, COLIIA1, vitamin D receptor (VDR), colony-stimulating factor 1, calcium-sensing receptor, epidermal growth factor (EGF), estrogen receptor 1 (ESR1), fibrillin type 1, insulin-like growth factor 1, interleukin-1 alpha (IL-1alpha), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-11 (IL-11), osteopontin, parathyroid hormone (PTH), PTH-related peptide, PTH receptor type 1 (PTHR1), transforming growth factor-beta 1, and tumor necrosis factors alpha and beta. Sixty-four microsatellites lying close to or within these genes were investigated for linkage with BMD. Using the program MapMaker/Sibs there was suggestive evidence of linkage between BMD and PTHR1 (maximum LOD score obtained [MLS] 2.7-3.5). Moderate evidence of linkage was also observed with EGF (MLS 1.8), COLIA1 (MLS 1.7), COLIIA1/VDR (MLS 1.7), ESR1 (MLS 1.4), IL-1alpha (MLS 1.4), IL-4 (MLS 1.2), and IL-6 (MLS 1.2). Variance components analysis using the program ACT, correcting for proband-wise ascertainment, also showed evidence of linkage (p </= 0.05) at markers close to or within the candidate genes IL-1alpha, PTHR1, IL-6, and COLIIA1/VDR. Further studies will be required to confirm these findings, to refine the location of gene responsible for the observed linkage, and to screen the candidate genes targeted at these loci for mutations.
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PMID:Suggestive linkage of the parathyroid receptor type 1 to osteoporosis. 1062 57

Interleukin-6 (IL-6) is a pleiotropic cytokine that interacts with its receptor in prostate cells, thus regulating proliferative response and differentiation. It also activates the human androgen receptor in prostate cancer cell lines. In order to assess the significance of these findings in vivo, the expression of key elements of the IL-6 signalling pathway, IL-6 and its receptor, was investigated in tissue samples obtained on radical prostatectomy from prostate cancer patients. IL-6 immunohistochemistry was performed on 17 frozen prostate cancer specimens. IL-6 receptor immunostaining was evaluated in 21 paraffin-embedded prostate tumour specimens. In both groups, adjacent areas of high-grade prostatic intraepithelial neoplasia and benign tissue were also investigated. In benign prostatic epithelium, IL-6 was localized predominantly in basal cells, whereas in prostate cancer tissues more IL-6-positive glandular cells were identified. No IL-6 expression was detected in stromal cells on immunohistochemistry, although IL-6 protein was measured in the supernatants obtained from cultured stromal cells by ELISA. IL-6 receptor was expressed in benign prostatic tissue in both epithelial and stromal cells. Furthermore, IL-6 receptor expression was observed in all tumour specimens investigated and the majority of Gleason patterns analysed had more than 50% of cells showing a positive reaction. IL-6 and IL-6 receptor expression patterns in high-grade prostatic intraepithelial neoplasia lesions were similar to those observed in tumour tissues. Taken together, the results of the present study imply that there are paracrine and autocrine IL-6 loops in benign and neoplastic prostate.
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PMID:Immunohistochemical localization of interleukin-6 and its receptor in benign, premalignant and malignant prostate tissue. 1087 41

Prostate cancer, while initially dependent on androgens for proliferation, progresses to an androgen-independent state. Evidence has been accumulating that interleukin-6 (IL-6) may contribute to prostate cancer progression. Serum levels of IL-6 correlate with prostate tumor burden and patient morbidity. The prostate tissue itself appears to be a source of IL-6 and its receptor. Furthermore, experimental data suggest that IL-6 is an autocrine and paracrine growth factor for androgen-independent prostate cancer cell lines. For example, inhibition of IL-6, with anti-IL-6 antibody, sensitizes androgen-independent prostate cancer cells to chemotherapeutic agents in vitro. Finally, IL-6 activates a variety of signal transduction cascades, some which stimulate androgen receptor activity, in prostate cancer cells. These data suggest that targeting IL-6 may have multiple benefits in prostate cancer patients.
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PMID:Interleukin-6 and prostate cancer progression. 1131 17

Interleukin-6 (IL-6) induces prostate cancer (CaP) cell proliferation in vitro. Several lines of evidence suggest that IL-6 may promote CaP progression through induction of an androgen response. In this work, we explored whether IL-6 induces androgen responsiveness through modulation of androgen receptor (AR) expression. We found that in the absence of androgen, IL-6 increased prostate-specific antigen (PSA) mRNA levels and activated several androgen-responsive promoters, but not the non-androgen responsive promoters in LNCaP cells. Bicalutamide, an antiandrogen, abolished the IL-6 effect and IL-6 could not activate the PSA and murine mammary tumor virus reporters in AR-negative DU-145 and PC3 cells. These data indicate the IL-6 induces an androgen response in CaP cells through the AR. Pretreatment of LNCaP cells with SB202190, PD98059, or tyrphostin AG879 [p38 mitogen-activated protein kinase (MAPK), MAP/extracellular signal-regulated protein kinase kinase 1/2, and ErbB2 MAPK inhibitors, respectively) but not wortmannin (PI3-kinase inhibitor) blocked IL-6-mediated induction of the PSA promoter, which demonstrates that IL-6 activity is dependent on a MAPK pathway. Finally, IL-6 activated the AR gene promoter, resulting in increased AR mRNA and protein levels in LNCaP cells. These results demonstrate that IL-6 induces AR expression and are the first report of cytokine-mediated induction of the AR promoter. Taken together, our results suggest that IL-6 induces AR activity through both increasing AR gene expression and activating the AR in the absence of androgen in CaP cells. These results provide a mechanism through which IL-6 may contribute to the development of androgen-independent CaP.
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PMID:Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. 1141 May 19

Sex hormones have a broad range of actions in regulating very diverse systems through life as well as critical reproductive and growth processes. Sex hormone biology in its satisfaction of the early demands of species survival and reproductive advantage may be leading a destructive process resulting in frailty and the less desirable aspects of aging that may, in men, be termed andropause. One important system associated directly with aging is interleukin-6, which increases as androgens decline. This may be taking place regardless of androgen receptor activity. It is currently acknowledged that androgens are the first but not the only possible treatment for andropause. There is an acute appreciation of the potentially undesirable impact of androgens on the biology of prostate cancer, as well as, possibly, the cardiovascular system. Most authors agree that careful evaluation and surveillance of the prostate must attend androgen therapy in aging men.
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PMID:Andropause: coming of age for an old concept? 1173 96


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