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)

The two carcinoma cell lines HeLa and HTM-29 show different behaviour in terms of interleukin-6 (IL-6) production. Analyses of secreted IL-6 by ELISA and of IL-6 mRNA by reverse transcription-PCR revealed that, whereas HeLa cells produced high levels of IL-6 in response to tumour necrosis factor-alpha (TNF-alpha) and IL-1beta, the HTM-29 cell line failed to produce both IL-6 protein and mRNA. Nevertheless, the transcription factors nuclear factor-kappaB (NF-kappaB) and NF-IL6, the main factors involved in IL-6 gene transcriptional activation by cytokines, were activated in both cell lines after treatment with TNF-alpha or IL-1beta. In order to verify that the lack of IL-6 expression in HTM-29 cells was not due to an endogenous IL-6 gene deficiency or to IL-6 mRNA instability, we carried out transient transfection assays with an IL-6 promoter-reporter construct. Strong activation of the IL-6 promoter by cytokines could be observed in HeLa cells, whereas no induction could be detected in cytokine-treated HTM-29 cells. These cytokines induced a very strong stimulation of NF-kappaB-mediated transcription in HeLa cells transfected with a kappaB luceriferase reporter construct, whereas no induction could be detected in cytokine-stimulated HTM-29 cells. Thus IL-6 promoter repression in HTM-29 cells probably results from a failure of cytokine-activated NF-kappaB to exert its transactivating activities. Western blotting experiments demonstrated that the lack of NF-kappaB-mediated transcription was not due to increased expression of IkappaB (inhibitor of NF-kappaB) proteins in HTM-29 cells. Co-transfection experiments with the kappaB Luc reporter construct and the CBP [CREB (cAMP response element binding protein) binding protein] expression vector showed that the impairment in NF-kappaB-dependent transcription did not result from a deficiency in the co-activator CBP. Interestingly, both NF-kappaB-mediated transcription and IL-6 promoter activation could be restored in HTM-29 cells by transfection with RelA. Furthermore, CBP could have a significant synergistic effect on exogenous RelA-mediated transcription. Since sequencing of the endogenous relA gene did not reveal any mutation, it is likely that repression of NF-kappaB-mediated transcription results from negative cross-talk between NF-kappaB and another nuclear factor specifically expressed or regulated by TNF-alpha in HTM-29 cells.
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PMID:Regulation of interleukin-6 gene expression by pro-inflammatory cytokines in a colon cancer cell line. 1090 37

Interleukin-6 (IL-6) is a pleiotropic cytokine that is involved in many autoimmune and inflammatory diseases. Transcriptional control of IL-6 gene expression is exerted by various compounds, among which glucocorticoids are the most potent antiinflammatory and immunosuppressive agents currently in use. Glucocorticoids exert their transrepressive actions by negatively interfering with transcription factors, such as nuclear factor-kappaB (NF-kappaB) and AP-1. Both factors make use of the coactivator cAMP response element-binding protein (CREB)-binding protein (CBP) to enhance their transcriptional activities, which led to the hypothesis that a mutual antagonism between p65 or c-Jun and activated glucocorticoid receptor (GR) results from a limited amount of CBP. Recently, we showed that glucocorticoid repression of NF-kappaB-driven gene expression occurs irrespective of the amount of coactivator levels in the cell. In the current study, we extend this observation and demonstrate that also AP-1-targeted gene repression by glucocorticoids is refractory to increased amounts of nuclear coactivators. From results with Gal4 chimeric proteins we conclude that glucocorticoid repression occurs by a promoter-independent mechanism involving a nuclear interplay between activated GR and AP-1, independently of CBP levels in the cell.
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PMID:Glucocorticoid repression of AP-1 is not mediated by competition for nuclear coactivators. 1115 29

Kaposi's sarcoma-associated herpesvirus (KSHV) is an important pathogen in Kaposi's sarcoma and abnormal lymphoproliferation. KSHV open reading frame 50 (ORF50), a homolog of the Epstein-Barr virus immediate-early gene product RTA, activates early and late gene transcription in the KSHV lytic cycle, and its expression is closely correlated with KSHV-related diseases. ORF50 interacts with the cellular proteins CBP and histone deacetylase and represses p53-induced apoptosis through a CBP-related mechanism. We show here that KSHV ORF50 also interacts with STAT3. ORF50 stimulated transcription of STAT-driven reporter genes, and interleukin-6 and v-Src further activated this stimulating effect of ORF50. Physical association of STAT3 and ORF50 required the carboxyl-terminal transactivation domain of ORF50 and multiple regions within STAT3. ORF50 recruited STAT3 to the nucleus and induced the dimerization of STAT3 monomers in the absence of STAT3 phosphorylation. We show here that KSHV ORF50 activates STAT3-mediated transcription through direct interaction without mediating tyrosine phosphorylation.
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PMID:Kaposi's Sarcoma-associated herpesvirus open reading frame 50 stimulates the transcriptional activity of STAT3. 1174 76

The related members of the interleukin-6 (IL-6) family of cytokines, leukemia inhibitory factor (LIF), oncostatin M (OSM) and IL-6 are inflammatory mediators that control differentiated cell functions as well as proliferation. The cellular responsiveness to these cytokines is largely determined by the expression of the appropriate receptor proteins. The receptor expression profile for each cell type is established during differentiation and is often altered during oncogenic transformation. Since inhibition of histone deacetylases (HDAC) has the potential to re-activate epigenetically silenced genes, we asked whether inhibition of HDAC enhances the expression of IL-6 cytokine receptors and, thus, increase desirable cytokine responses. We demonstrate that treatment with FR901228 (FR), an HDAC inhibitor, increases the responsiveness to LIF in different cell types, including normal fibroblasts, epithelial cells, macrophages and splenocytes, as well as various tumor cell lines. Depending on the cell type, FR treatment also enhances the responsiveness to OSM and IL-6. These effects involve a transcriptional induction of the cytokine receptor subunits LIFRalpha, OSMRbeta, gp130, or the transcription factor STAT3. FR-specific induction of LIFRalpha occurs independently of de novo protein synthesis and cell proliferation and is mediated in part by the CBP/p300 coactivator. Chromatin immunoprecipitation experiments indicate that the expression of LIFRalpha and gp130 genes correlates with the level of acetylated histone 3 associated with the receptor promoter regions. The FR-stimulated expression of IL-6-type cytokine receptors in certain tumor cells also provided improved conditions for suppression of cell growth by taking advantage of the growth inhibitory effect of these cytokines.
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PMID:FR901228, an inhibitor of histone deacetylases, increases the cellular responsiveness to IL-6 type cytokines by enhancing the expression of receptor proteins. 1221 67

We have shown that non-pathogenic enteric Gram-negative Bacteroides vulgatus induces RelA phosphorylation, NF-kappaB activation, and proinflammatory gene expression in primary and intestinal epithelial cell (IEC) lines. We now demonstrate the transient induction of nuclear phospho-RelA (day 3) followed by persistent activation of phospho-Smad2 (days 3 and 7) in IEC from mucosal tissue sections of B. vulgatus-monoassociated rats, indicating that both NF-kappaB and transforming growth factor-beta1 (TGF-beta1) signaling are induced in vivo following bacterial colonization. Interestingly, TGF-beta1 inhibited B. vulgatus- and lipopolysaccharide (LPS)-induced NF-kappaB transcriptional activity as well as interleukin-6 (IL-6) mRNA accumulation and protein secretion in IEC. The inhibitory effect of TGF-beta1 is mediated independently of B. vulgatus/LPS-induced IkappaBalpha, Akt, and RelA phosphorylation as well as NF-kappaB DNA binding activity. Moreover, the specific histone deacetylase inhibitor trichostatin A blocked B. vulgatus/LPS-induced histone acetylation/phosphorylation (Lys-9/Ser-10) and reversed TGF-beta1-mediated inhibition of IL-6 gene expression. Chromatin immunoprecipitation analysis revealed that B. vulgatus/LPS-induced RelA recruitment to the IL-6 promoter is inhibited by TGF-beta1 treatment. Adenoviral delivery of Smad7 and dominant negative Smad3 (SmadDelta3) reversed the TGF-beta1-mediated inhibition of NF-kappaB transcriptional activity and NF-kappaB recruitment to the IL-6 promoter. In addition, TGF-beta1 and Ad5Smad3/4 prevent B. vulgatus/LPS-induced CBP/p300 and p65 nuclear co-association. We concluded that the TGF-beta1/Smad signaling pathway helps maintain normal intestinal homeostasis to commensal luminal enteric bacteria by regulating NF-kappaB signaling in IEC through altered histone acetylation.
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PMID:Transforming growth factor-beta 1 inhibits non-pathogenic Gram negative bacteria-induced NF-kappa B recruitment to the interleukin-6 gene promoter in intestinal epithelial cells through modulation of histone acetylation. 1267 95

InKine Pharmaceutical Co. is developing an oral compound, CBP 1011, for the treatment of immune thrombocytopenic purpura (ITP) [Hematrol] and for the treatment of inflammatory bowel disorders, ulcerative colitis and Crohn's disease (Colirest). This profile has been selected from R&D Insight, a pharmaceutical intelligence database produced by Adis International Ltd. CBP 1011 or medroxyprogesterone, is a progesterone agonist and inhibits pro-inflammatory mediators such as interleukin-6 and tumour necrosis factor (TNF). CBP 1011 was originally developed by CorBec Pharmaceuticals, which in 1997 was aquired by Panax and then intergrated into InKine Pharmaceuticals. According to a company spokesperson, InKline is pursuing outlicensing opportunities for Hematrol since the company's current commercial focus is on gastrointestinal products. In June 2000, InKine announced the completion of a study comparing the bioavailability of a commercially viable tablet formulation of CBP 1011 to the original capsule formulation that is currently being used in the company's phase III studies in patients with idiopathic thrombocytopenic purpura. Preliminary results from this study indicate that the bioavailability of the tablet formulation does not differ significantly from that of the capsule formulation. The trial enrolled ITP patients (i) who are HIV positive, (ii) who are chronic ITP sufferers despite having had a splenectomy, (iii) who are older, or (iv) who have less severe thrombocytopenia. In preclinical trials, CBP 1011 was shown to decrease lymphocyte infiltration into the bowel compared with the control. Studies also show that it possibly offers safety benefits over steroid therapies. In June 2001, InKine commenced enrolment for a pivotal phase III trial in the treatment of Crohn's disease. This randomised, double-blind trial will enrol approximately 250 patients and will compare two doses of CBP 1011 (400 and 1000mg) with placebo. In April 2003, the US Patent and Trademark Office granted InKine Pharmaceutical a 'Notice of Allowance' for the 'Method of Treating Inflammatory Conditions with Progesterone or Progesterone Analogs'. This patent for medroxyprogesterone (Colirest) provides InKine patent protection for the use of Colirest in treating patients with Crohn's disease, ulcerative colitis, proctitis, microscopic colitis, allergic eosinophilic gastroenteritis, food allergies, drug-induced oesophagitis, coeliac disease, recurrent polyps and haemorrhoids. The patent protection also covers Colirest in a variety of delivery forms such as tablet, enema, suppository, foam, gel, ointment and suspension.
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PMID:CBP 1011: Colirest, Hematrol. 1284 89

The activation of the transcription factor NF-kappaB is central to the control of the cellular response triggered by many stimuli. Once released from the inhibitory molecule IkappaB, NF-kappaB is translocated to the nucleus, and it has to be phosphorylated to activate transcription. In zeta protein kinase C (PKC)-deficient cells, NF-kappaB is transcriptionally inactive and the phosphorylation of the RelA subunit in response to tumor necrosis factor (TNF-alpha) is severely impaired. In vitro assays showed that zetaPKC directly phosphorylates RelA. Here we demonstrate that Ser311 accounts for zetaPKC phosphorylation of RelA and that this site is phosphorylated in vivo in response to TNF-alpha. Also, an inactivating mutation of that residue severely impairs RelA transcriptional activity, blocks its anti-apoptotic function and abrogates the interaction of RelA with the co-activator CBP as well as its recruitment, and that of RNA polymerase II (Pol II) with the interleukin-6 (IL-6) promoter. The interaction of endogenous CBP with endogenous RelA is inhibited in zetaPKC-/- cells, as well as the binding of Pol II to the IL-6 promoter. These results demonstrate the mechanism whereby zetaPKC regulates NF-kappaB activation in vivo.
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PMID:Essential role of RelA Ser311 phosphorylation by zetaPKC in NF-kappaB transcriptional activation. 1288 25

The androgen receptor co-activator CREB (cAMP-response element binding protein)-binding protein (CBP) enhances androgen receptor activity after stimulation by androgenic hormones and androgen receptor antagonists. The aim of the present study was to investigate the regulation of CBP expression by steroid and peptide hormones in prostate cancer. For this purpose, LNCaP cells were treated with the synthetic androgen methyltrienolone (R1881), epidermal growth factor, insulin-like growth factor-I or interleukin-6 (IL-6). CBP protein and mRNA expression were studied by western blotting and real-time PCR, respectively. CBP expression was also investigated in tissue specimens obtained from 26 patients with therapy-resistant carcinoma of the prostate. In LNCaP cells, CBP protein was down-regulated by R1881 or IL-6. The non-steroidal anti-androgen bicalutamide antagonized the effects of R1881 and the Janus kinase inhibitor AG 490 reversed the effects of IL-6. In contrast, neither R1881 nor IL-6 caused any effect on CBP expression in the PC-3 cell line. In LNCaP cells, the inhibition of CBP expression by R1881 or IL-6 was also observed at the mRNA level. CBP protein was detected in all 26 specimens by immunohistochemistry. The results suggest that up-regulation of CBP during androgen ablation may be relevant to the failure of endocrine therapy in patients with prostate carcinoma.
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PMID:The androgen receptor co-activator CBP is up-regulated following androgen withdrawal and is highly expressed in advanced prostate cancer. 1537 87

Human androgen receptor (AR) associates with coactivator or corepressor proteins that modulate its activation in the presence of ligand. Early studies on AR coactivators in carcinoma of the prostate were hampered because of lack of respective antibodies. Investigations at mRNA level revealed that most benign and malignant prostate cells express common coactivators. AR coactivators SRC-1 and TIF-2 are up-regulated in tissue specimens obtained from patients who failed prostate cancer endocrine therapy. Increased expression of these coactivators is associated with enhanced activation of the AR by the adrenal androgen dehydroepiandrosterone. Similar association between AR coactivator expression and high prostate cancer grade and stage was reported for RAC-3 (SRC-3). The transcriptional integrator CBP was detected in clinical specimens representing organ-confined prostate cancer, lymph node metastases and tumour cell lines. Agonistic effect of the nonsteroidal antiandrogen hydroxyflutamide was strongly potentiated in prostate cells transfected with CBP cDNA. A functional homologue of CBP, p300, is implicated in ligand-independent AR activation by interleukin-6. The AR coactivator Tip60, which is up-regulated by androgen ablation, is recruited to the promoter of the prostate-specific antigen gene in the absence of androgen in androgen-independent prostate cancer sublines. It was proposed that the cofactor ARA70 is a specific enhancer of AR action. However, research from other laboratories has demonstrated interaction between ARA70 and other steroid receptors. Although in some cases dominant-negative coactivator mutants inhibited proliferation of prostate cancer cells in vitro, confirmation from in vivo tumour models is missing. In summary, several abnormalities in AR coactivator expression and function are associated with prostate cancer progression.
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PMID:Expression and function of androgen receptor coactivators in prostate cancer. 1566 89

Several options for the endocrine treatment of non-organ-confined prostate cancer are available. They include surgical or medical removal of androgenic hormones or administration of non-steroidal anti-androgens. However, tumour progression after a period of remission of the disease inevitably occurs in virtually all patients. The androgen receptor (AR) is, in various tumour models, implicated in the development of therapy resistance but molecular mechanisms that by-pass the receptor have also been described. Adaptation mechanisms relevant to tumour recurrence include up-regulation of AR mRNA and protein, overexpression of AR coactivators, increased activation of mutated receptors by steroids and anti-androgens, and ligand-independent activation. For research studies, sublines that respond to but do not depend on androgen for their proliferation were generated. Coactivators SRC-1, TIF-2, RAC3, p300, CBP, Tip60, and gelsolin are highly expressed in endocrine therapy-resistant prostate cancer. AR point mutations are increasingly detected in relapsed cancers and contribute to the failure of endocrine therapy in a subgroup of patients. Ligand-independent activation of the AR by HER-2/neu and interleukin-6 is associated with activation of the signalling pathway of mitogen-activated protein kinase. Increased activity of intracellular kinases may affect cellular events in both an AR-dependent and -independent manner. Mitogen-activated protein kinases are strongly phosphorylated in endocrine therapy-resistant prostate tumours. Similarly, activation of the AR by phosphorylated protein kinase B, Akt, has also been reported in prostate cancer. Activation of the Akt pathway contributes to increased survival of prostate tumour cells.
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PMID:Mechanisms of endocrine therapy-responsive and -unresponsive prostate tumours. 1594 99

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