UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The mechanism of repression of the interleukin-6 (IL-6) promoter by 17 beta-estradiol (E2) was investigated in cells transfected with wild-type (wt) or mutant estrogen receptor (ER) expression vectors. In transient transfection experiments, IL-1-induced activation of the IL-6 promoter was efficiently inhibited by wt ER. However, estrogen receptors carrying mutations within or over-lapping with the DNA binding domain did not repress IL-6 promoter activity. A mutant receptor lacking the N-terminal transactivator function-1 but retaining the C-terminal transactivator function-2 also repressed activation of the IL-6 promoter. Our recent experiments indicate the requirement for both the nuclear factor (NF)-IL6 and the NF-kappa B sites in the IL-6 promoter for activation by IL-1. We now show that activation of the IL-6 promoter, elicited by a combination of NF-IL6 and the p65 subunit of NF-kappa B, can be inhibited by the wt receptor but not by a receptor containing a mutation in its DNA binding domain. Although a deletion within the DNA binding domain of ER abolished the repressor function of the receptor, a chimeric receptor ER-GR CAS1, in which the DNA binding domain of ER was swapped with the complementary region from the glucocorticoid receptor, retained the inhibitory effects on the IL-6 promoter. This was in contrast to the absolute dependence of ER on its own DNA binding domain for activation of typical estrogen response element-containing promoters, as reported previously by other investigators. Furthermore, the repression of the IL-6 promoter by a combination of ER and E2, unlike activation of estrogen response elements by the same combination, did not appear to be mediated via high affinity binding of the receptor to the promoter. In functional experiments, the transactivator function of ER was totally inhibited by overexpression of p65 and to a lesser extent by that of NF-IL6. These results indicate that ER may repress gene expression in the absence of high affinity DNA binding.
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PMID:Down-modulation of interleukin-6 gene expression by 17 beta-estradiol in the absence of high affinity DNA binding by the estrogen receptor. 817 11

We studied the effects of interleukin-1 alpha (IL-1) and interleukin-6 (IL-6) on MCF-7 breast cancer cells to determine whether these cytokines act additively/synergistically to alter cell growth and metabolism. We found that IL-1 alone (1000 units/ml) inhibited cell growth to a greater degree (83.8%) than IL-6 alone (29.2%, P < 0.001). The combination of IL-1 + IL-6 caused greater inhibition of growth (92.9%, P < 0.02) than either cytokine alone. The additive effect was dose dependent for both IL-1 and IL-6. IL-1 and IL-6 also antagonized estradiol (10(-9) M) stimulated growth. Antagonism by the combination was greater than for either cytokine alone (P < 0.001). IL-1 or IL-6 alone each down-regulated the estrogen receptor (36.7%, P < 0.01, and 23.2%, P < 0.05, respectively), but the combination IL-1 + IL-6 did not cause a significantly greater effect than IL-1 alone. Neither IL-1 or IL-6 blocked estradiol stimulation of progesterone receptor (PR) synthesis; however, the combination IL-1 + IL-6 increased PR content by 28.4% (P < 0.01). IL-1, but not IL-6, increased secretion of transforming growth factor-beta (TGF-beta) by 2.45-fold over 72 h (P < 0.01). The increase was time dependent (detectable at 24 h) and dose dependent (maximum increase of 5.3-fold, 10,000 units/ml, P < 0.02). IL-1-induced TGF-beta secretion was blocked by estradiol (10(-9) M). Neither cytokine altered secretion of insulin-like growth factor-1. These findings indicate that IL-1 and IL-6 act additively to inhibit growth in the absence or presence of estradiol and modulate the estrogen receptor and progesterone receptor content of these cells. TGF-beta may mediate the effects of IL-1; however, other pathways appear to be required for the additive effects of these cytokines.
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PMID:Interleukin-1 alpha and interleukin-6 act additively to inhibit growth of MCF-7 breast cancer cells in vitro. 845 20

Interleukin-6 (IL-6) is a multifunctional cytokine thought to be a key factor in post-menopausal osteoporosis, given its ability to induce osteoclast maturation and its down regulation by estrogens. We have previously shown that the effects of TNFalphaand estradiol on the human IL-6 promoter were dependent on a region of the promoter containing a C/EBP site and a NF-kappaB site. To define the molecular mode of action of estrogens, we performed gel shift assays with this DNA fragment as a probe, and nuclear extracts from TNFalpha-induced HeLa, MCF7 and Saos2 cells. Several induced complexes specifically bound the probe. The use of various competitor DNA suggested that most of the complexes detected contained NF-kappaB factors, and that C/EBP site binding factors were important for the overall binding to the probe. Addition of in vitro translated human estrogen receptor (hER) impaired the binding of three complexes in HeLa cells and two complexes in MCF7 and Saos2 cells. Competition experiments suggested that the NF-kappaB site was necessary for the effect of hER. The use of antisera against NF-kappaB and C/EBP proteins showed that the target complexes of hER contained the c-rel proto-oncogene product and to a lesser extent, the RelA protein. Taken together, these data show that hER impairs TNFalphainduction of IL-6 by preventing c-rel and, to a lesser extent, RelA proteins binding to the NF-kappaB site of the IL-6 promoter.
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PMID:Estrogen receptor impairs interleukin-6 expression by preventing protein binding on the NF-kappaB site. 917 Oct 95

Estrogens are the most effective agents available for preventing osteoporosis, and their principal role in bone metabolism is the inhibition of interleukin-6 (IL-6) production in osteoblasts and bone marrow stromal cells. We examined the mechanism of inhibitory effect of estrogens on the 190 bp proximal promoter of the IL-6 gene. Promoter activity induced by transfection of both NF-kappaB p65 subunit and NF-IL6 was decreased by 45% by estradiol (E2)-estrogen receptor (ER) complexes. The inhibitory effect of E2 was also observed on a mutant IL-6 promoter in which the NF-IL6 binding site was disrupted. E2 repressed the wild-type promoter activity induced by NF-kappaB p65 subunit alone, but had no effect on that induced by NF-IL6 alone. These findings suggested that estrogens inhibit IL-6 production by interfering with the function of NF-kappaB rather than that of NF-IL6. The ER mutant, HE19, which does not contain the A/B domain, repressed the induction by NF-kappaB to the same extent as wild-type ER HE0, whereas the effect of C-terminal deletion mutant, HE21, was only marginal. The antiestrogen, 4-hydroxytamoxifen (OHT), had no effect on IL-6 promoter activity, suggesting that E2-induced conformational change of the hormone binding domain plays an important role in protein-protein interaction between ER and NF-kappaB. E2 had no effect on the nuclear translocation of NF-kappaB, and electrophoretic mobility shift assay showed that the presence of E2-ER complexes did not affect the ability of NF-kappaB to bind to specific DNA sequences.
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PMID:Characterization of mechanisms of interleukin-6 gene repression by estrogen receptor. 918 53

The cytokine interleukin-6 (IL-6), a key mediator of immune and acute phase responses of the liver, has also been implicated in uterine functions. Estrogens are potent repressors of IL-6 production by uterine stromal cells. In the endometrial adenocarcinoma cell line Ishikawa, phorbol ester-induced activation of the IL-6 promoter was inhibited to basal levels by 17 beta-estradiol (E2) in a wild-type receptor-dependent fashion. Although tamoxifen has been shown to have estrogenic effects on the endometrium, it did not inhibit induction of the IL-6 promoter. We previously showed that inhibition of IL-6 gene expression by E2 does not involve high-affinity binding of the estrogen receptor (ER) to IL-6 DNA. We now report that the ER can directly interact with the transcription factors NF-IL6 and NF-kappa B and can inhibit their ability to bind DNA which might be the molecular basis for repression of IL-6 gene expression by estrogens.
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PMID:Repression of interleukin-6 gene expression by 17 beta-estradiol: inhibition of the DNA-binding activity of the transcription factors NF-IL6 and NF-kappa B by the estrogen receptor. 919 8

The primary culture of rat luteal cells and their long-term maintenance have been difficult. Low cellular yields have limited the possibility for the study of gene regulation in luteal cells. The goal of this study was to develop a cell line to serve as a model by which to study the expression and regulation of various genes specific to luteal cells. We attempted to develop a luteal cell line by transformation of large luteal cells through infection with a temperature-sensitive simian virus (SV-40 tsA209) mutant that has a temperature-sensitive mutation required for the maintenance of cell transformation. We report here the successful establishment of such a cell line, designated GG-CL cells. Large luteal cells were purified to homogeneity by flow cytometry from corpora lutea of day 14 pregnant rats, cultured for 24 h, and then infected with the SV-40 tsA209 mutant virus. Transformed cells were maintained at the permissive temperature (33 C) until colonies were identified. Several colonies of transformed cells were isolated and passaged. They multiplied at 33 C and formed multilayers. At the nonpermissive temperature (40 C), cells reverted to the normal differentiated phenotype similar to the primary luteal cells in culture. To determine whether GG-CL cells express the genes found in normal luteal cells, messenger RNA (mRNA) expression was examined by either Northern analysis or RT-PCR with primers specific to each mRNA. GG-CL cells were found to express receptors for interleukin-6 and glucocorticoid, as well as the newly discovered estrogen receptor-beta (ER-beta) and the orphan nuclear receptor nur 77. No receptors for ER-alpha, progesterone, LH, or PRL could be detected. This cell line also expressed 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), but not cholesterol side-chain cleavage cytochrome P450 (P450scc), 3beta-hydroxysteroid dehydrogenase, or aromatase cytochrome P450 (P450arom). Although the cells did not express the PRL receptor, they did express Janus kinase (JAK2) and signal transducers and activators of transcription (Stat5b), and, when transfected with the PRL receptor, they responded to PRL with a marked inhibition in 20alpha-HSD mRNA expression. In addition, estradiol enhanced ER-beta expression in a dose-dependent manner whereas cAMP stimulation caused a marked and rapid increase in the expression of the orphan receptor nur 77. In summary, a temperature-sensitive cell line was successfully established from the large luteal cells of rat corpora lutea. These cells express key genes encoding enzymes and receptors inherent to this defined luteal cell population and respond to stimulation by PRL, estradiol, and cAMP.
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PMID:Establishment and characterization of a simian virus 40-transformed temperature-sensitive rat luteal cell line. 952 80

A male patient with abnormal postpubertal bone elongation was shown earlier to have a mutation in both alleles of the estrogen receptor, resulting in a nonfunctional gene. Marrow stromal fibroblasts (MSFs) derived from this patient were called HERKOs (human estrogen receptor knock outs), and in order to obtain continuous HERKO cell lines, they were immortalized using a recombinant adenovirus-origin-minus SV40 virus. MSFs are unique cells because they support hematopoesis and contain a mixed population of precursor cells for bone, cartilage, and fat. Three established cell lines (HERKO2, HERKO4, and HERKO7) were characterized and compared with the heterogeneous population of nonimmortalized HERKOs for their osteogenic potential. We performed Northern analysis of matrix genes implicated in bone development and metabolism and an in vivo bone formation assay by transplanting the cells subcutaneously into immunodeficient mice. All three HERKO lines expressed high amounts of collagen 1A1, osteopontin, osteonectin, fibronectin, decorin, biglycan, and alkaline phosphatase. Except for osteopontin, expression of these genes was slightly lower compared with nonimmortalized HERKOs. In the in vivo bone formation assay, the heterogeneous population of nonimmortalized HERKOs formed bone with high efficiency, while the HERKO lines induced a high-density, bone-like matrix. Finally, all HERKO cell types secreted high levels of insulin-like growth factor I and interleukin-6 into the culture medium relative to cells of normal human subjects. In summary, these lines of HERKO cells retain several of the phenotypic traits of MSFs after immortalization, including matrix and cytokine production, and provide a valuable source of a unique human material for future studies involving estrogen action in bone and bone marrow metabolism.
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PMID:Immortalization and characterization of bone marrow stromal fibroblasts from a patient with a loss of function mutation in the estrogen receptor-alpha gene. 955 60

Many compounds of plant origin with the ability to bind to the estrogen receptor have been identified in the last decades. There is evidence that the consumption of some of these phytoestrogens may have beneficial effects but it also seems possible that others may act as endocrine disrupters. For this reason there is a need to characterise the estrogenic potency of these substances. In vitro test systems offer the possibility to screen compounds very efficiently. Routinely in use and widespread for the determination of estrogenicity are: (I) receptor binding assays, (II) cell-proliferation assays (E-screens), (III) reporter gene assays, and (IV) the analysis of the regulation of endogenous estrogen sensitive genes in cell lines. The basis of all these test systems are molecular mechanisms which are involved in the classical estrogen action. In addition, in the last years several test systems for the investigation of non-classical estrogenic effects have been established. An example for such an effect is the modulation of the expression of interleukin-6, a cytokine that appears to be a key molecule in the osteoporotic process, by estrogens. Summarising the advantages and the issues of all presented in vitro test systems, it seems to be evident that only the analysis of results obtained in a combination of several in vitro test systems may validly predict effects in vivo.
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PMID:In vitro test systems for the evaluation of the estrogenic activity of natural products. 1023 61

Idoxifene, a selective estrogen receptor modulator, was evaluated in male and female rats with adjuvant-induced arthritis (AA). AA was induced in Lewis rats with Mycobacterium butyricum in paraffin oil injected into the base of the tail, and the animals were treated with idoxifene prophylactically (days 0-21) or therapeutically (days 10-21). Efficacy was determined by measurements of paw inflammation, bone mineral content, and bone mineral density (BMD) with dual X-ray absorptiometry and by histological evaluation. Serum interleukin-6 levels were measured as a marker of the anti-inflammatory effects of the compound. Estrogen was included for comparison and was administered at 5 mg/kg, three times a week s.c. Prophylactic treatment of male AA rats with idoxifene at 10, 3, and 1 mg/kg and estrogen at 5 mg/kg significantly inhibited paw inflammation. There was improved joint integrity measured by BMD and reduced serum interleukin-6 levels in animals treated with 10 mg/kg/day idoxifene. Idoxifene and estrogen were as effective for AA in female Lewis rats as in male rats, significantly inhibiting paw inflammation and improving BMD. Histological evaluation of the tibiotarsal joints of female rats treated with 10 mg/kg showed protection of bone, cartilage, and soft tissue. Therapeutic treatment with either idoxifene or estrogen (starting on day 10 of disease) of male and female Lewis rats also was effective in reducing paw inflammation in these animals, although the effect was much less than that observed with the prophylactic dosing protocol.
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PMID:Idoxifene, a novel selective estrogen receptor modulator, is effective in a rat model of adjuvant-induced arthritis. 1056 64

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