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)

The human glycoprotein hormone alpha-gene is transcriptionally activated by cAMP in placental cells. We have shown that the novel hypothalamic peptide, pituitary adenylate cyclase activating polypeptide, PACAP-38, significantly stimulates intracellular cAMP levels (12-fold increase; P < 0.001) in JEG-3 choriocarcinoma cells. Regulation of alpha-promoter activity was assessed using both the chloramphenicol acetyl transferase (CAT) and the luciferase (LUC) reporter gene systems. alpha-CAT activity was significantly stimulated by PACAP-38 (4-fold increase; P < 0.05) at 24 h with a similar stimulation being seen with a LUC expression vector. The kinetics of stimulation of the alpha-promoter by PACAP-38 were similar to those seen with 8-Br-cAMP and vasoactive intestinal polypeptide (VIP), a peptide which shares 68% homology with PACAP-38. PACAP-38 also stimulated the production of IL-6 from JEG-3 cells with a time course of response similar to that of alpha-promoter transcription. We conclude that human placental choriocarcinoma cells possess functional receptors for PACAP-38, whose activation enhances cAMP formation, alpha-subunit gene transcription and interleukin-6 (IL-6) production.
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PMID:PACAP-38 positively regulates glycoprotein hormone alpha-gene expression in placental cells. 751 49

Human aromatase cytochrome P450 catalyzes the ultimate reaction in the estrogen biosynthetic pathway by coupling with another enzyme, NADPH-cytochrome P450 reductase, in the endoplasmic reticulum. The expression of the gene encoding the enzyme (CYP19) is regulated, in part, by tissue-specific promoters through the use of alternative-splicing mechanisms. Recently, we have localized a transcriptional activating element at positions -2141 to -2115 relative to the major cap site of the gene, by transient expression analyses in human BeWo choriocarcinoma cells using the bacterial chloramphenicol acetytransferase reporter gene ligated with CYP19 promoter sequences which regulate expression in this tissue. Here, we report the isolation of a cDNA encoding a DNA-binding protein which binds specifically to the regulatory element. The deduced amino-acid sequence of the insert is identical to that corresponding to the DNA-binding domain and the dimerization domain of a transcription factor, nuclear factor interleukin-6 (NF-IL6), a member of the CCAAT/enhancer-binding protein (C/EBP) family. Studies using specific antibodies against members of the C/EBP family demonstrate that NF-IL6 is the major nuclear factor binding to the regulatory element in BeWo cells; nevertheless. C/EBP alpha also seems to be involved. Disruption of the NF-IL6-binding site within the regulatory element resulted in the disappearance of the transcriptional enhancing activity of the element, indicating that NF-IL6 is at least one of the nuclear factor(s) which enhances transcription through binding to the cis-acting element. These results indicate the intrinsic importance of NF-IL6 in the transcriptional regulation of CYP19 expression.
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PMID:Identification of a transcriptional regulatory factor for human aromatase cytochrome P450 gene expression as nuclear factor interleukin-6 (NF-IL6), a member of the CCAAT/enhancer-binding protein family. 763 40

Interleukin 1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were assayed by 125I immunoradiometric assay in sera of 42 cases of vesicular mole (VM), 24 cases of choriocarcinoma and 23 normal pregnant women at their first trimester (controls). According to pathologic diagnosis and serial serum hCG beta assays, the cases with VM and choriocarcinoma were subdivided into remission and progressive tumor groups. The progressive tumor groups--both VM and choriocarcinoma--showed marked elevations of serum IL-1 beta, IL-6 and TNF alpha. For choriocarcinoma in remission this elevation was considerably less pronounced. The VM cases in remission had only a slight increase of the mean serum IL-6 value and none of the cases had elevated IL-1 beta or TNF values. These results may indicate that serum IL-1 beta and TNF-alpha assays are valuable biomarkers in the differential diagnosis of gestational trophoblastic disease (GTD). Moreover, normal values of these cytokines may rule out high-risk GTD, whereas markedly elevated values may indicate poor prognosis.
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PMID:Serum cytokines in gestational trophoblastic diseases. 771 55

Interleukin-6 (IL-6) stimulates the release of hCG from syncytiotrophoblast cells, but the effects of IL-6 and other cytokines on the release of placental lactogen (hPL) are unknown. To determine the effect of IL-6 on hPL release, we exposed an enriched fraction of trophoblast cells (prepared by the isopycnic centrifugation of enzymatically dispersed term placenta) continuously to IL-6 (500 U/ml) for up to 6 days. The amounts of hPL released by the IL-6-exposed cells during days 3 and 6 were 177.6 +/- 2.4% and 267.5 +/- 12.6% that of control cells, respectively (P < 0.0001 in each instance). In addition, the hPL messenger RNA (mRNA) contents of the IL-6-exposed cells after 3 and 6 days of exposure were 2.2- and 4.7-fold that of control cells. The stimulatory effect of IL-6 on hPL release and hPL mRNA levels was dose dependent, with a minimal effective dose of 50 U/ml. IL-1 beta, which is known to stimulate IL-6 production by human trophoblast cells, also stimulated dose-dependent increases in hPL release and hPL mRNA levels. IL-6 (500 U/ml) had no effect on trophoblast differentiation, but stimulated a 20-fold increase in hPL promoter activity in BeWo choriocarcinoma cells transfected transiently with a plasmid containing 2.3 kilobases of the hPL promoter coupled to the chloramphenicol acetyltransferase gene. In addition, BeWo cells exposed to IL-6 (500 U/ml) for 3 and 6 days contained 2.4- and 3.2-fold more hPL mRNA levels than control cells. Because placental macrophages and syncytiotrophoblast cells release IL-6, these results strongly suggest an autocrine/paracrine role for IL-6 in the regulation of hPL release. The increase in hPL release appears to be due at least in part to an increase in hPL gene expression.
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PMID:Interleukin-6 stimulates placental lactogen expression by human trophoblast cells. 803 20

Aromatase cytochrome P450 catalyses the reaction to convert androgens to estrogens by coupling with NADPH-cytochrome P450 reductase in the endoplasmic reticulum. The human aromatase cytochrome P450 gene (CYP19) is expressed in a variety of tissues under regulation of tissue-specific promoters. Previously, we localized a cell-type specific transcriptional enhancer element between -242 and -166 relative to the major cap site of the gene, by transient expression analysis in human BeWo choriocarcinoma cells. In the present study, we demonstrate that the enhancer element consists of two subelements, element I (located between -238 and -200), and element II (located between -196 and -176) as analysed by DNase I footprinting using the nuclear extracts of BeWo cells. The gel mobility shift assay shows that each of these subelements binds specific nuclear factor(s). The transient expression of the bacterial chloramphenicol acetyltransferase gene constructs involving the subelements in BeWo cells reveals that the elements activate reporter gene expression synergistically when present together, nevertheless each of the elements by itself also has an enhancer activity. The transient expression analysis further shows that element I is responsible for the transcriptional synergism with the binding site of a nuclear factor-interleukin-6 (NF-IL-6) (also known as CCAAT enhancer/binding protein beta), which is located between -2141 and -2115 relative to the major cap site of the gene. These results suggest that the enhancer element plays important roles in sustaining the high levels of CYP19 expression in placental cells in cooperation with other cis-acting transcritional regulatory elements.
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PMID:Cooperative regulation of the human aromatase cytochrome P450 gene transcription by placenta-specific cis-acting elements. 936 92

Serotonin (5-HT) is a prime candidate for studies of the interaction between the nervous and immune systems, since it is both an important neurotransmitter and released at high concentrations at sites of inflammation. Serotonergic neurotransmission is regulated by the 5-HT transporter (5-HTT), which determines the magnitude and duration of serotonergic responses. Since tumor necrosis factor alpha (TNF-alpha) and interleukin-6 are two inflammatory mediators that are central to the initiation of inflammation, we studied the impact of these cytokines on the 5-HTT. As model system we used a cell line which constitutively expresses the 5-HTT, namely the choriocarcinoma cell line JAR. We found that TNF-alpha enhances 5-HT uptake, with a doubling of the maximal velocity of uptake. Interleukin-6, on the other hand, had no effect. We thus show for the first time that the cytokine TNF-alpha modulates 5-HTT function. Furthermore, we propose a molecular mechanism for this effect. Since both 5-HT and TNF-alpha are elevated at sites of inflammation, TNF-alpha may act to renormalize 5-HT levels by way of its effect on the 5-HTT. This is especially important for the central nervous system, where the TNF-alpha effect shown here can aid in preventing disturbances of serotonergic neurotransmission.
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PMID:Enhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6. 975 20

Extravillous trophoblast cells resemble cancer cells with regard to their intrinsic invasiveness. They invade decidual tissue, but, unlike tumor cells, shut down their invasive properties, when they become inappropriate. Stimuli involved in the modulation of invasion, as well as their underlying signaling mechanisms require further clarification. We were especially interested in discovering signals capable of stimulating invasion in otherwise low-invasive cells involved in reproduction. Using the choriocarcinoma cell line Jeg-3 as a model, we have addressed the potential role of cytokine/growth factor-driven activation of signal transducer and activator of transcription 3 (STAT3) in this process. Jeg-3 cells were treated with various factors known to induce trophoblast proliferation, differentiation, migration, or invasiveness (insulin-like-growth-factor-II (IGF-II), hepatocyte growth factor (HGF), interleukin-6 (IL-6), and leukemia inhibitory factor (LIF)). Only LIF elicited strong tyrosine phosphorylation and specific DNA-binding activity of STAT3. It induced a significant acceleration of cell proliferation and promoted the capability of Jeg-3 cells to invade into an artificial extracellular matrix. Moreover, LIF influenced the expression pattern of proteases and protease inhibitors with potential relevance for invasiveness (downregulation of mRNA for tissue inhibitor of metalloproteinase 1 (TIMP-1) and upregulation of mRNA for caspase-4). In conjunction with earlier work, in which we found that STAT3 DNA-binding activity was increased in invasive cells (choriocarcinoma, first trimester trophoblasts) and absent in non-invasive cells (term trophoblasts), these findings suggest a connection between LIF-driven STAT3 activity and invasiveness of choriocarcinoma and trophoblast cells.
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PMID:Leukemia inhibitory factor triggers activation of signal transducer and activator of transcription 3, proliferation, invasiveness, and altered protease expression in choriocarcinoma cells. 1612 46

Amongst the interleukin-6 (IL-6) family of cytokines, leukemia inhibitory factor (LIF) has been shown to promote trophoblast invasion and proliferation. In the present study interleukin-11 (IL-11), another member of the IL-6 family, was investigated for its role in regulating invasion, migration and proliferation of JEG-3 choriocarcinoma cells. JEG-3 cells, like extra villous trophoblast (EVT), express mRNA transcripts encoding IL-11 and IL-11 receptor-alpha (IL-11Ralpha). Treatment of JEG-3 cells with IL-11 led to an increase in invasion across Matrigel extracellular matrix without an increase in proliferation. There was a dose-dependent increase in activation of STAT3 under the influence of IL-11 with maximum Tyr705 phosphorylation by 10min. In addition, treatment of JEG-3 cells with IL-11 for 24h led to an increase in expression of unphosphorylated STAT1 and STAT3. Analysis of the nuclear fraction showed an increased localization of STAT3 following IL-11 treatment while STAT1 was absent. Silencing the expression of STAT3 by siRNA caused a 25% reduction in invasion compared to control cells, however this was not significant. Furthermore, treatment of STAT3-silenced JEG-3 cells with IL-11 led to a significant increase in invasion compared to STAT3-silenced cells without cytokine, but this was not significant compared to non-transfected control cells. Silencing the expression of gp130 but not of IL-6R abrogated the increase in invasiveness of JEG-3 cells following IL-11 treatment. In conclusion, activation and upregulation of STAT3 appears to be critical for the IL-11-mediated increase in invasiveness of JEG-3 cells.
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PMID:Interleukin-11 increases invasiveness of JEG-3 choriocarcinoma cells by modulating STAT3 expression. 1971 5

Food-borne infections caused by Salmonella enterica species are increasing globally, and pregnancy poses a high risk. Pregnant mice rapidly succumb to S. enterica serovar Typhimurium infection. To determine the mechanisms involved, we addressed the role of inflammation and bacterial burden in causing placental and systemic disease. In vitro, choriocarcinoma cells were a highly conducive niche for intracellular S. Typhimurium proliferation. While infection of mice with S. Typhimurium wild-type (WT) and mutant (Delta aroA and Delta invA) strains led to profound pathogen proliferation and massive burden within placental cells, only the virulent WT S. Typhimurium infection evoked total fetal loss and adverse host outcome. This correlated with substantial placental expression of granulocyte colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) and increased serum inflammatory cytokines/chemokines, such as G-CSF, IL-6, CCL1, and KC, evoked by WT S. Typhimurium infection. In contrast, infection with high doses of S. Typhimurium Delta aroA, despite causing massive placental infection, resulted in reduced inflammatory cellular and cytokine response. While S. Typhimurium WT bacteria were dispersed in large numbers across all regions of the placenta, including the deeper labyrinth trophoblast, S. Typhimurium Delta aroA bacteria localized primarily to the decidua. This correlated with the widespread placental necrosis accompanied by neutrophil infiltration evoked by the S. Typhimurium WT bacteria. Thus, the ability of Salmonella to localize to deeper layers of the placenta and the nature of inflammation triggered by the pathogen, rather than bacterial burden, profoundly influenced placental integrity and host survival.
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PMID:Salmonella enterica serovar Typhimurium-induced placental inflammation and not bacterial burden correlates with pathology and fatal maternal disease. 2095 76

Proviral insertion in murine (PIM) lymphoma proteins are mainly regulated by the Janus Kinase/Signal Transducer Activator of Transcription (JAK/STAT) signaling pathway, which can be activated by members of the Interleukin-6 (IL-6) family, including Leukemia Inhibitory Factor (LIF). Aim of the study was to compare PIM1, PIM2 and PIM3 expression and potential cellular functions in human first and third trimester trophoblast cells, the immortalized first trimester extravillous trophoblast cell line HTR8/SVneo and the choriocarcinoma cell line JEG-3. Expression was analyzed by qPCR and immunochemical staining. Functions were evaluated by PIM inhibition followed by analysis of kinetics of cell viability as assessed by MTS assay, proliferation by BrdU assay, and apoptosis by Western blotting for BAD, BCL-XL, (cleaved) PARP, CASP3 and c-MYC. Apoptosis and necrosis were tested by flow cytometry (annexin V/propidium iodide staining). All analyzed PIM kinases are expressed in primary trophoblast cells and both cell lines and are regulated upon stimulation with LIF. Inhibition of PIM kinases significantly reduces viability and proliferation and induces apoptosis. Simultaneously, phosphorylation of c-MYC was reduced. These results demonstrate the involvement of PIM kinases in LIF-induced regulation in different trophoblastic cell lines which may indicate similar functions in primary cells.
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PMID:PIM kinases 1, 2 and 3 in intracellular LIF signaling, proliferation and apoptosis in trophoblastic cells. 2872 93


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