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 immediate early genes are regulated by a variety of extracellular signals, including pleiotropic cytokines. The effects of the testicular cytokines, interleukin-6 (IL-6) and interferon-gamma (IFN-gamma), on signal transducers and activators of transcription 3 and 1 (STAT-3 and STAT-1) and on c-fos gene expression in primary Sertoli cells are suggestive of their roles in differential function. Using the tyrosine phosphorylation inhibitor, genistein, and electrophoretic mobility shift assay, we show that IL-6 and IFN-gamma induce nuclear factor STAT-3 and STAT-1 DNA-binding activity to the sis-inducible element of c-fos in a genistein-dependent pathway. Quantitative solution hybridization, Northern blot, and nuclear run-on analysis show that differential induction of c-fos, junB, and c-myc messenger RNA (mRNA) by these cytokines occur at transcriptional levels. IL-6 stimulates c-fos mRNA levels by 6-fold while increasing junB levels by 2-fold. IFN-gamma increases c-fos message 2-fold, but has no effect on junB mRNA levels. Furthermore, genistein treatment blocks the induction of c-fos and junB gene expression, demonstrating that tyrosine phosphorylation of STAT proteins is involved in the cytokine regulation of the Sertoli immediate early genes. H7, a serine/threonine phosphorylation inhibitor, also blocks c-fos gene induction by IL-6 and IFN-gamma, but does not affect the DNA-binding activities of STAT-3 and STAT-1. Finally, IL-6 treatment of Sertoli cells (3-6 h) increases the amounts of activating protein-1 binding to activating protein-1 element and c-myc transcription.
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PMID:Transcriptional regulation of Sertoli cell immediate early genes by interleukin-6 and interferon-gamma is mediated through phosphorylation of STAT-3 and STAT-1 proteins. 920 12

Infiltration of the glomerular mesangium by monocytes and macrophages is a central pathologic feature in various forms of glomerulonephritis. Dependent on the presence and activity of local survival factors, monocytes may undergo apoptosis. Therefore, we looked for the interaction between cultured human mesangial cells (HMC) and intact, necrotic or apoptotic monocytic cells with different stages of programmed cell death (U937 cells and blood-derived human monocytes) and the possible evoked secretory responses of HMC. Interleukin-6 (IL-6) synthesis of HMC after a two hour co-culture with late apoptotic U937 cells was significantly increased (505 +/- 55 pg/ml) as compared to intact U937 cells (349 +/- 27 pg/ml; HMC alone, 319 +/- 62 pg/ml), and was further elevated after 20 hours (815 +/- 108 pg/ml). U937 cells alone, after incubation in HMC-conditioned medium or after coincubation with HMC, did not produce any detectable IL-6. A high mesangial IL-6 synthesis in response to apoptotic U937 cells was dependent on the cellular contact between HMC and U937 and could not be mimicked by apoptotic U937 culture supernatants. Radiolabeling studies indicated that HMC bound (16.6 +/- 2.4%) and ingested (12.5 +/- 1.9%) apoptotic U937 cells to a much higher amount as compared to intact U937 (5.3 +/- 2.0% binding; 5.0 +/- 1.1% phagocytosis). Binding and ingestion of monocytic cells undergoing apoptosis was confirmed by morphologic studies using electron microscopy. Incubation of HMC with a blocker of the CD36/ vitronectin receptor (VnR) dependent recognition mechanism of phagocytes for apoptotic leukocytes (RGDS peptide) did not alter binding, phagocytosis or IL-6 synthesis of HMC in response to apoptotic U937. Phospho-L-serine as an antagonist of the phosphatidylserine (PS) mediated recognition pathway for apoptotic cell disposal was able to reduce binding and IL-6 production by HMC but not phagocytosis. Thus, binding of apoptotic monocytic cells by HMC rather than ingestion may be the prerequisite for a stimulated secretory response. To elucidate whether binding and phagocytosis of particles in general might stimulate HMC to produce IL-6, we looked for mesangial IL-6 production after binding and ingestion of opsonized zymosan particles. In this case, IL-6 synthesis was markedly down-regulated. Furthermore, HMC proliferated after zymosan treatment, whereas after apoptotic cell uptake the mesangial cell number remained constant. In conclusion, apoptotic monocytic cells provoked an enhanced mesangial IL-6 synthesis by a PS-dependent recognition mechanism. This secretory response may have secondary implications for humoral or cellular processes within the mesangium.
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PMID:Induction of mesangial interleukin-6 synthesis by apoptotic U937 cells and monocytes. 926 86

We recently reported that insulin stimulation results in the serine phosphorylation of STAT3 (signal transducer and activator of transcription-3). In the present study, we identified serine 727 as the site of insulin-stimulated STAT3 serine phosphorylation. This phosphorylation event occurs independent of tyrosine phosphorylation. Furthermore, interleukin-6-induced tyrosine phosphorylation can occur independent of serine phosphorylation, demonstrating that these two phosphorylation pathways are mechanistically unrelated. Selective activation of the JNK and p38 family of mitogen-activated protein (MAP) kinases by anisomycin treatment did not result in the phosphorylation of STAT3. In contrast, activation of the ERK MAP kinase pathway with both insulin and osmotic shock resulted in the serine phosphorylation of STAT3. In addition, expression of a dominant-interfering Ras mutant (N17Ras) or treatment with the specific MEK inhibitor (PD98059) prevented the insulin stimulation of STAT3 serine phosphorylation. Blockade of ERK activation by expression of the MAP kinase phosphatase (MKP-1) had no effect on insulin-stimulated STAT3 serine phosphorylation. Together, these data demonstrate that the insulin-stimulated serine phosphorylation of STAT3 occurs by a MEK-dependent pathway that is independent of ERK activation.
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PMID:Signal transducer and activator of transcription-3 serine phosphorylation by insulin is mediated by a Ras/Raf/MEK-dependent pathway. 932 21

Recent studies have indicated that serine phosphorylation regulates the activities of STAT1 and STAT3. However, the kinase(s) responsible and the role of serine phosphorylation in STAT function remain unresolved. In the present studies, we examined the growth factor-dependent serine phosphorylation of STAT1 and STAT3. We provide in vitro and in vivo evidence that the ERK family of mitogen-activated protein (MAP) kinases, but not JNK or p38, specifically phosphorylate STAT3 at serine 727 in response to growth factors. Evidence for additional mitogen-regulated serine phosphorylation is also provided. STAT1 is a relatively poor substrate for all MAP kinases tested both in vitro and in vivo. STAT3 serine phosphorylation, not its tyrosine phosphorylation, results in retarded mobility of the STAT3 protein on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Importantly, serine 727 phosphorylation negatively modulates STAT3 tyrosine phosphorylation, which is required for dimer formation, nuclear translocation, and the DNA binding activity of this transcriptional regulator. Interestingly, the cytokine interleukin-6 also stimulates STAT3 serine phosphorylation, but in contrast to growth factors, this occurs by an ERK-independent process.
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PMID:STAT3 serine phosphorylation by ERK-dependent and -independent pathways negatively modulates its tyrosine phosphorylation. 934 14

Unlike monoclonal antibodies, clinical application of bispecific antibodies has so far lagged behind because of difficult, low-yield production techniques as well as considerable toxicity attributed to bispecific antibody preparations containing immunoglobulin-Fc parts and anti-CD3 homodimers. These difficulties were overcome by recombinant generation of a bispecific single-chain antibody (bscAb) joining two single-chain Fv fragments via a five-amino-acid glycine-serine linker. The anti-CD3 specificity directed against human T cells was combined with another specificity against the epithelial 17-1A antigen. The following domain arrangement was critical in this individual case to obtain a fully functional bscAb: VL17-1A-VH17-1A-VHCD3-VLCD3. The bscAb was expressed in chinese hamster ovary cells with a yield of 15 mg/l culture supernatant whereas numerous attempts to obtain a functional protein expression in Escherichia coli failed. The low-molecular-mass bispecific construct (60 kDa) could easily be purified by its C-terminal histidine tail. The antigen-binding properties are indistinguishable from those of the corresponding univalent single-chain Fv fragments as shown by enzyme immunoassay and flow cytometry. We could show that the bscAb, which lacks Fc parts and anti-CD3 homodimers is highly cytotoxic for 17-1A positive tumor cells in nanomolar concentrations and in the presence of human T cells. Most remarkable, it does not stimulate T lymphocyte proliferation in the absence of tumor cells and, moreover, does not induce CD25 up-regulation and the secretion of potentially toxic lymphokines such as tumor necrosis factor alpha, interleukin-6 and interferon gamma. Maximal cytotoxicity (51Cr release) was achieved without notable costimulation and was not further enhanced by adding costimulatory signals such as those delivered by anti-CD28 antibodies. CD8+ as well as CD4+ T cell subpopulations were recruited to exert cytotoxicity against tumor cells with different kinetics. CD8+ cells induced high 51Cr release within 4 h while CD4+ cells required a 20-h incubation. The systemic application of the 17-1A/CD3-bscAb could be a major improvement in therapy against disseminated micrometastatic tumor cells. A prospective, randomized clinical trial showing that an anti-17-1A monoclonal antibody could prolong survival of colorectal cancer patients after 5 and 7 years, warrants an assessment of the clinical efficacy of this bscAb exhibiting a 1000-fold higher specific cytotoxicity against tumor cells in vitro.
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PMID:Construction and biological activity of a recombinant bispecific single-chain antibody designed for therapy of minimal residual colorectal cancer. 943 72

The activation of sphingomyelinase and the generation of ceramide has been proposed to mediate tumor necrosis factor-alpha (TNF-alpha)-induced nuclear factor (NF)-kappaB activation through its second messenger ceramide. Ceramide may also be an important regulator of cell growth, senescence, and apoptosis. Aberrant cell proliferation and apoptosis have been implicated in the rampant fibroblast proliferation and pannus formation characteristic of rheumatoid arthritis. However, the role of TNF-alpha and the sphingomyelinase pathway in the process have not been determined. The objective of this study was to determine whether TNF-alpha activates the sphingomyelin pathway in human synovial fibroblasts (HSF) and the potential role of ceramide in HSF proliferation and apoptosis. Cultured human synovial fibroblasts were stimulated with exogenous TNF-alpha, sphingomyelinase, and ceramide. Apoptosis was assessed by cell morphology and annexin V labeling. NF-kappaB and stress kinase pathway activation were determined by immunoblotting techniques. Sphingomyelinase activation was determined by quantitation of sphingomyelin and ceramide radioactivity in [14C]serine-prelabeled HSF cells. The addition of TNF-alpha (50 ng/ml) to HSF did not elicit detectable sphingomyelinase activation. TNF-alpha was shown to activate NF-kappaB (p65 translocation and degradation of IkappaBalpha) and the stress kinase pathway (phosphorylation of ATF-2, p38, and c-jun). In contrast, exogenous ceramide had no effect on these signaling pathways nor did ceramide stimulate the generation of interleukin-6 or interleukin-8. High concentrations of ceramide (> or =25 micromol/L) were cytotoxic, whereas lower concentrations of ceramide inhibited cell cycle progression. Thus, although TNF-alpha stimulates the NF-kappaB and stress kinase pathways in HSF, these effects of TNF-alpha are not associated with sphingomyelinase turnover or induction of apoptosis.
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PMID:Synovial fibroblasts and the sphingomyelinase pathway: sphingomyelin turnover and ceramide generation are not signaling mechanisms for the actions of tumor necrosis factor-alpha. 946 77

The acute phase response is the answer of the organism to disturbances of its physiological homeostasis. It consists of a local and a systemic reaction. The latter is characterized by dramatic changes in the concentration of some plasma proteins called acute phase proteins. Interleukin-6 (IL-6) has been identified in vitro and in vivo as the major hepatocyte stimulating factor. Subsequently, additional hepatocyte stimulating factors, such as leukemia inhibitory factor, oncostatin-M, interleukin-11 and ciliary neurotrophic factor have been discovered. IL-t and related cytokines belong to the so-called alpha-helical cytokine family characterized by four antiparallel helices. IL-6 and IL-6-type cytokines exert their action via plasma membrane receptor complexes consisting of specific cytokine binding subunits and a common signal transducing protein gp130. In this presentation we focus on structure/function studies of IL-6, its receptor subunits gp80 and gp130, the internalization of the ligand/receptor complex and a recently elucidated signal transduction pathway. We have shown that protein tyrosine kinases of the JAK family are associated with the cytoplasmic domain of gp130 and are activated in response to IL-6. Subsequently, the transcription factors--named STATs (signal transducers and activators of transcription)--STAT1 alpha and STAT3 are transiently recruited to the cytoplasmic domain of gp130, where they become tyrosine phosphorylated by JAK kinases. In addition to the tyrosine phosphorylation we have observed that IL-6 also induces a serine phosphorylation of STAT3. This modification occurs with a delayed time-course as compared to the tyrosine phosphorylation and is inhibited by the protein kinase inhibitor H7. We propose that the STAT3 serine phosphorylation is required for transactivation of IL-6 target genes which is also inhibited by H7.
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PMID:Interleukin-6 and related cytokines: effect on the acute phase reaction. 955 28

Interleukin-6 (IL-6) is the major growth factor for human myeloma cells, exerting its effect through the IL-6 receptor (IL-6R). A soluble form of IL-6R (sIL-6R) has been identified, which increases the sensitivity of myeloma cells to IL-6. In patients with multiple myeloma (MM), serum concentrations of sIL-6R are elevated and associated with poor prognosis. The present study was undertaken to determine whether proteolytic cleavage of IL-6R could contribute to sIL-6R release from human myeloma cells, and also to identify the class of proteinase responsible for this event. Human myeloma cell lines were shown to express IL-6R upon their surface and also to release sIL-6R into culture supernatants. In addition, phorbol 12-myristate 13-acetate (PMA) stimulated a loss of IL-6R from the cell surface, with a corresponding increase in the concentration of sIL-6R in the supernatant. Inhibitors of serine and cysteine proteinases, and tissue inhibitor of metalloproteinase (TIMP) -1 and TIMP-2, were shown to have no effect on the magnitude of sIL-6R release. In contrast, TIMP-3 and a hydroxamate-based metalloproteinase inhibitor (BB-94), inhibited both constitutive and PMA-induced release of sIL-6R. Myeloma cells freshly isolated from the bone marrow of a patient with MM were also shown to express IL-6R upon their surface, and to shed this receptor in response to PMA. These data demonstrate that increased proteolytic cleavage of IL-6R, mediated by a non-matrix-type metalloproteinase, is likely to contribute to the elevated concentrations of sIL-6R found in the serum of patients with MM. Inhibition of sIL-6R release by hydroxamate-based metalloproteinase inhibitors may represent a novel therapeutic approach to the treatment of MM.
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PMID:Human myeloma cells shed the interleukin-6 receptor: inhibition by tissue inhibitor of metalloproteinase-3 and a hydroxamate-based metalloproteinase inhibitor. 967 43

Interleukin-6 (IL-6) belongs to the family of the "four-helix bundle" cytokines. The extracellular parts of their receptors consist of several Ig- and fibronectin type III-like domains. Characteristic of these receptors is a cytokine-binding module consisting of two such fibronectin domains defined by a set of four conserved cysteines and a tryptophan-serine-X-tryptophan-serine (WSXWS) sequence motif. On target cells, IL-6 binds to a specific IL-6 receptor (IL-6R), and the complex of IL-6.IL-6R associates with the signal transducing protein gp130. The IL-6R consists of three extracellular domains. The NH2-terminal Ig-like domain is not needed for ligand binding and signal initiation. Here we have investigated the properties and functional role of the third membrane proximal domain. The protein can be efficiently expressed in bacteria, and the refolded domain is shown to be sufficient for IL-6 binding. When complexed with IL-6, however, it fails to associate with the gp130 protein. Since the second and the third domain together with IL-6 can bind to gp130 and induce signaling, our data demonstrate the ligand binding function of the third domain and point to an important role of the second domain in complex formation with gp130 and signaling.
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PMID:The membrane proximal cytokine receptor domain of the human interleukin-6 receptor is sufficient for ligand binding but not for gp130 association. 969 99

Gene activation and cellular differentiation induced by interleukin-6 (IL-6) and transcription factor Stat3 are suppressed by several factors, including ionomycin, granulocyte/macrophage-colony-stimulating factor, and phorbol 12-myristate 13-acetate (PMA), that block IL-6-induced Stat3 activation. These inhibitory agents activate mitogen activated protein kinases (MAPKs), and thus the role of MAPKs in the mechanism of inhibition of Stat3 activation was investigated. Inhibition of IL-6-induced Stat3 activation by PMA and ionomycin was rapid (within 5 min) and did not require new RNA or protein synthesis. Inhibition of Stat3 DNA-binding activity and tyrosine phosphorylation by PMA, ionomycin, and granulocyte/macrophage-colony-stimulating factor was reversed when activation of the extracellular signal-regulated kinase (ERK) group of MAPKs was blocked by using specific kinase inhibitors. Expression of constitutively active MEK1, the kinase that activates ERKs, or overexpression of ERK2, but not JNK1, inhibited Stat3 activation. Inhibition of Stat3 correlated with suppression of IL-6-induction of a signal transducer and activator of transcription (STAT)-dependent reporter gene. In contrast to IL-6, activation of Stat3 by interferon-alpha was not inhibited. MEKs and ERKs inhibited IL-6 activation of Stat3 harboring a mutation at serine-727, the major site for serine phosphorylation, similar to inhibition of wild-type Stat3, and inhibited Janus kinases Jak1 and Jak2 upstream of Stat3 in the Jak-STAT-signaling pathway. These results demonstrate an ERK-mediated mechanism for inhibiting IL-6-induced Jak-STAT signaling that is rapid and inducible, and thus differs from previously described mechanisms for downmodulation of the Jak-STAT pathway. This inhibitory pathway provides a molecular mechanism for the antagonism of Stat3-mediated IL-6 activity by factors that activate ERKs.
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PMID:Rapid inhibition of interleukin-6 signaling and Stat3 activation mediated by mitogen-activated protein kinases. 973 97

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