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)

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-beta (TGF-beta) superfamily and are crucial factors in the process of bone formation. Despite knowledge on their wide distribution and expression, however, there is very little information on the biological factors that affect gene transcription of these osteoinductive agents. To investigate this aspect of BMP gene regulation we have studied the effect of a number of factors known to affect osteogenic cells. Northern analysis showed modulation of the expression of BMP-2 and BMP-4 mRNAs in two human osteosarcoma cell lines, MG63 and Saos-2, by prostaglandin E2 (PGE2), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), interferon-alpha (IFN-alpha), retinoic acid and 1,25(OH)2 vitamin D3. mRNA expressions of the normally used "housekeeping genes", glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and beta-actin, were found to be susceptible to influence by some of the factors used. Hence, an oligo(dT)15-18 probe was used to reliably estimate the relative quantities of mRNA present for normalization of data. In general, all factors down-regulated mRNA expressions of BMP-2 and BMP-4 in MG63 cells. IL-6 completely abolished detectable expression of BMP-2 mRNA, which was also greatly reduced by IL-1beta, retinoic acid and 1,25(OH)2 vitamin D3. PGE2 had similar influences on BMP-2 and BMP-4 expressions, showing reductions to approximately 60% of normal. In Saos-2 cells only 1,25(OH)2 vitamin D3 had any great effect on BMP-2 expression, which was down-regulated to approximately 60% of control values. BMP-4 was down-regulated by IFN-alpha (approximately 60%) and IL-1beta (approximately 20%). We conclude that BMPs are subject to regulation by a variety of factors and that this is dependent on the stage of the cell in the osteogenic lineage. Furthermore, the use of GAPDH and beta-actin genes as "housekeeping genes" in expression-modulation studies must be treated with care.
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PMID:Modulation of bone morphogenetic protein-2 and bone morphogenetic protein-4 gene expression in osteoblastic cell lines. 987 11

Ebola virus infection is highly lethal and leads to severe immunosuppression. In this study, we demonstrate that infection of human umbilical vein endothelial cells (HUVECs) with Ebola virus Zaire (EZ) suppressed basal expression of the major histocompatibility complex class I (MHC I) family of proteins and inhibited the induction of multiple genes by alpha interferon (IFN-alpha) and IFN-gamma, including those coding for MHC I proteins, 2'-5' oligoadenylate synthetase [2'-5'(A)N], and IFN regulatory factor 1 (IRF-1). Induction of interleukin-6 (IL-6) and ICAM-1 by IL-1beta was not suppressed by infection with EZ, suggesting that the inhibition of IFN signaling is specific. Gel shift analysis demonstrated that infection with EZ blocked the induction by IFNs of nuclear proteins that bind to IFN-stimulated response elements, gamma activation sequences, and IFN regulatory factor binding site (IRF-E). In contrast, infection with EZ did not block activation of the transcription factor NF-kappaB by IL-1beta. The events that lead to the blockage of IFN signaling may be critical for Ebola virus-induced immunosuppression and would play a role in the pathogenesis of Ebola virus infection.
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PMID:Ebola virus selectively inhibits responses to interferons, but not to interleukin-1beta, in endothelial cells. 1007 8

To compare virological, biochemical, and immune responses to human lymphoblastoid interferon (IFN-alpha) and human fibroblast interferon (IFN-beta) in patients with chronic hepatitis C virus (HCV) infection, 120 patients were randomly assigned to three groups (group A, 60 patients receiving IFN-alpha, 6 million units (MU) once a day, daily for one month and thrice weekly for five months; group B, 40 patients receiving 6 MU IFN-beta once a day daily for two months; and group C, 20 patients receiving 3 MU IFN-beta twice a day (6 MU/day) daily for two months). Serum soluble interleukin-2 receptor (sIL-2R) and interleukin-6 (IL-6) levels were measured by enzyme-linked immunosorbent assay. Patients with sustained clearance of serum HCV RNA detected by polymerase chain reaction (PCR) at six months after IFN treatment were defined as having complete response to IFN treatment. A low level of HCV RNA (< or = 10(4) copies/50 microl, measured by competitive PCR) and HCV RNA of genotype 2a were favorable factors for a complete response to both IFNs. Complete response in group A treatment was strongly associated with early HCV RNA clearance, in contrast with group B. A significantly higher HCV RNA negativity at the second week from start of treatment was noted in group C (80.0%), compared with groups A (41.6%) and B (27.5%). sIL-2R levels rose in each group during IFN administration. In group C, alanine aminotransferase (ALT) and IL-6 levels were remarkably elevated. These findings indicate that timing of serum HCV RNA negativity in sustained response differs between IFN-alpha and IFN-beta administrations and that early HCV RNA clearance was induced by twice-a-day IFN-beta treatment.
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PMID:Differences between interferon-alpha and -beta treatment for patients with chronic hepatitis C virus infection. 1008 Jan 58

Interferons are able to enhance the expression of carcinoembryonic antigen (CEA) on tumour cells, allowing improved tumour targeting. In this report the hypothesis is tested that combinations of cytokines may further increase the tumour antigen expression. The combination of both IFN-gamma and IFN-alpha with interleukin-6 demonstrated a significant additive effect on the CEA-expression. This was found by quantitatively analysing the CEA-expression on human colorectal tumour cells by flow cytometry. It is concluded that combinations of cytokines show the potential of inducing tumour antigen expression for improved tumour targeting.
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PMID:In vitro upregulation of carcinoembryonic antigen expression by combinations of cytokines. 1040 10

Telomeres, G-rich structures at the ends of chromosomes are essential for maintaining chromosomal integrity. Most tumor cells contain telomerase, a ribonucleoprotein that elongates telomeric repeats, and it plays an essential role in indefinite proliferation. To better understand regulatory mechanisms of telomerase, in relationship with apoptosis and the cell cycle, we examined telomerase activity in PCM6, an interleukin-6 (IL-6)-responsive, interferon-alpha (IFN-alpha)-sensitive multiple myeloma cell line, using a PCR-based assay. When PCM6 cells were cultured in serum-free media, the addition of IFN-alpha resulted in apoptosis of the cells, but with no influence on telomerase activity. When IFN-alpha was added to the culture with serum plus rIL-6 after serum deprivation, G1-S transition was inhibited and telomerase activity was lower compare to findings in culture with no IFN-alpha. Dose response experiments of rIL-6 and IFN-alpha, and the measurement of telomerase activity of sorted cells in S-phase using CD71, demonstrated a higher activity of telomerase in the samples which contained a larger proportion of cells in S-phase. These data indicate that regulation of telomerase activity is closely related to cell cycle status, in particular cells in S-phase have an high telomerase activity. While telomeres play an important role in cellular senescence, the regulation of telomerase is independent from apoptotic signals induced by IFN-alpha in myeloma cells.
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PMID:Telomerase activity in myeloma cells is closely related to cell cycle status, but not to apoptotic signals induced by interferon-alpha. 1043 72

The in vitro mixed lymphocyte reaction (MLR) is a useful model to study alloresponsiveness to histocompatibility antigens. Secretion of different cytokine proteins in the supernatant of allo-MLR cultures has been reported in a few studies. We studied the levels of the cytokines interferon gamma (IFN-gamma) and interleukin-6 (IL-6), IL-10, IL-12, and IL-18 in the supernatant in allo-MLR by ELISA assay. Supernatant levels of IFN-y, IL-6, IL-10, and IL-18 were detected at 12 h after MLR and markedly increased thereafter. In contrast, secretion of IL-12 was detected after 48-72 h. These results suggested that IFN-gamma production depended on IL-18 in the early phase of MLR and depended on both IL-18 and IL-12 in the late phase. An antibody (Ab) neutralizing test was also performed. The levels of IFN-gamma were significantly downregulated after the addition of anti-IL-18 Ab, anti-IL-12 Ab, or anti-IFN-y Ab, and the levels of IL-12 were significantly downregulated after the addition of anti-IL-12 Ab and anti-IL-18 Ab. Treatment with these Ab did not suppress IL-6 production at all. The two-way MLR showed the same tendency as the one-way MLR. These results suggest the importance of IL-18 and IL-12 in allogeneic cell interactions and also suggest the usefullness of these Ab as regulators of alloresponsiveness.
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PMID:Involvement of interleukin-18 (IL-18) in mixed lymphocyte reactions (MLR). 1050 49

The present study was designed to investigate the growth regulatory effects of cytokines in UT-OC-3 ovarian cystadenocarcinoma cells in vitro. The effects of interleukin-6 (IL-6), interferons alpha (IFN-alpha) and gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumour necrosis factor alpha (TNF-alpha), and transforming growth factor beta1 (TGF-beta1) were investigated by (125)I-deoxyuridine ((125)IUdR) incorporation assay. In order to understand better the molecular mechanisms of the observed effects, the activation of DNA-binding proteins was studied by electrophoretic mobility shift assay. In addition, cellular DNA was tested by fragmentation analysis to determine if the most growth inhibitory cytokines are able to induce programmed cell death (apoptosis). After 48h in culture, TGF-beta1, TNF-alpha, IFN-alpha and IL-6 showed a clear inhibitory effect on (125)IUdR incorporation (P<0.005), and IFN-gamma and GM-CSF caused even more significant inhibition (P<0.001). IFN-alpha and IFN-gamma were both growth inhibitory after 72h in culture (P<0.005). Similarly, GM-CSF induced a slight inhibition (P<0.05), whereas TGF-beta1 and TNF-alpha almost blocked DNA synthesis (P<0.001) after 72h. IL-6 had no statistically significant effect on cell proliferation after 72h. Transcription factors AP-1 and NF-kappaB were both constitutively expressed in UT-OC-3 cells. The binding activity of AP-1 was found to be stimulated by the growth inhibitory cytokines, TGF-beta1 and TNF-alpha, and the binding of NF-kappaB was stimulated by TNF-alpha. Apoptosis does not seem to be induced by any of these cytokines in the UT-OC-3 ovarian cancer cell model.
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PMID:Regulation of UT-OC-3 ovarian carcinoma cells by cytokines: inhibitory effects on cell proliferation and activation of transcription factors AP-1 and NF-kappaB. 1075 82

Double stranded RNA (dsRNA), an intermediate that is common during viral infection, directly induces much higher levels of expression of interleukin-6 (IL-6) mRNA than does the cytokine IL-1beta. Interferon alpha (IFNalpha) by itself does not induce expression of IL-6; nonetheless, IFNalpha pretreatment dramatically enhances IL-6 induction by dsRNA but not by IL-1beta. Mutation of either the activating transcription factor/cyclic AMP response element binding protein (ATF/CREB) or the NF-IL-6 binding element within the IL-6 promoter eliminates most responsiveness of CAT reporter constructs to either dsRNA or to IL-1beta. IFNalpha pretreatment partially restores responsiveness to dsRNA but not to IL-1beta when either the ATF/CREB site or the NF-IL-6 site is mutated, but at least one of these sites must be intact for responsiveness to be restored. Mutation of the kappaB binding site in the IL-6 promoter eliminates responsiveness to either IL-1beta or to dsRNA, and pretreatment with IFNalpha does not restore any responsiveness. Incubation with dsRNA leads to a decrease in protein translation, especially in cells that have been pretreated with IFNalpha. Nonetheless, IFNalpha pretreatment followed by dsRNA leads to very high IL-6 protein levels. These studies demonstrate that major differences exist in the induction of IL-6 at both the mRNA and protein levels by dsRNA compared to cytokines and that IFNalpha pretreatment selectively enhances IL-6 induction by dsRNA but not by IL-1beta. The high levels of IL-6 expression that result when cells encounter class I IFN prior to dsRNA suggest a mechanism for a heightened host response to viral infection with heightened production of this pleotropic cytokine.
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PMID:Interferon-alpha synergistically enhances induction of interleukin-6 by double stranded RNA in HeLa cells. 1078

Although interleukin-6 (IL-6) alone does not induce the expression of IFN stimulated genes (ISG), a low dose priming of cells with IL-6 strongly enhances the cellular responses to interferon-alpha (IFN-alpha). This effect of IL-6 is not due to superstimulation of the JAK-STAT pathway. Rather, IL-6 induces expression of ISGF3 gamma (p48), a subunit of the multimeric transcription factor ISGF3. As a result IFN-alpha robustly activates gene transcription in IL-6 primed cells. We have shown earlier that the transcription of ISGF3 gamma gene is regulated through a novel element GATE (gamma-IFN activated transcriptional element). We show here IL-6 induces the ISGF3 gamma gene through GATE. Transcription factor C/EBP-beta is required for inducing ISGF3 gamma gene expression through GATE. A mutant C/EBP-beta inhibits the IL-6 inducible ISGF3 gamma gene expression through GATE. Together, these results establish a molecular basis for the synergy between IFNs and IL-6.
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PMID:Interleukin-6 modulates interferon-regulated gene expression by inducing the ISGF3 gamma gene using CCAAT/enhancer binding protein-beta(C/EBP-beta). 1100 86

As survival regulation is a key process in multiple myeloma biology, we have studied the Bcl-2 family proteins that can be regulated by three myeloma cell survival factors: interleukin-6 (IL-6), interferon-alpha (IFN-alpha) and insulin-like growth factor (IGF-1). Eleven myeloma cell lines, whose survival and proliferation are dependent on addition of IL-6, variably expressed 10 anti-apoptotic or pro-apoptotic proteins of the Bcl-2-family. When myeloma cells from four cell lines were IL-6 starved and activated with IL-6 or IFN-alpha, we observed that only Mcl-1 expression was up-regulated with myeloma cell survival induction. Nor was obvious regulation of these 10 pro-apoptotic or anti-apoptotic proteins found with IGF-1, another potent myeloma cell survival factor. Our results indicate that the myeloma cell survival activity of IL-6 linked to Bcl-xL regulation cannot be generalized and emphasize that Mcl-1 is the main target of IL-6 and IFN-alpha stimulation. However, other changes in the activity of the Bcl-2 protein family or other apoptosis regulators must be identified to elucidate the IGF-1 action mechanism. Cell Death and Differentiation (2000) 7, 1244 - 1252.
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PMID:Regulation of Bcl-2-family proteins in myeloma cells by three myeloma survival factors: interleukin-6, interferon-alpha and insulin-like growth factor 1. 1117 62


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