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 mediates its pleiotropic effects by interacting with its membrane bound receptor (gp80) or the soluble counterpart gp54, resulting in activation of a complex that includes the transducer protein gp130. We have generated a polyclonal antibody against the rat soluble IL-6 receptor (anti-rat sIL-6R) in rabbits. By Western blot analysis we show that purified anti-rat sIL-6R IgG antibody reacts specifically with recombinant rat sIL-6R generated from E. coli, baculovirus or adenovirus expression systems. Anti-rat sIL-6R inhibited IL-6-induced acute phase protein synthesis in rat (H35) but not human (HepG2) hepatoma cells, and did not affect stimulation of those cells by Oncostatin-M. Conversely, on the mouse hybridoma B9 cell line, IgG anti-rat sIL-6R showed a dose-dependent stimulation of proliferation. Fab fragments of this antibody did not stimulate, but abrogated IL-6-mediated hepatoma cell stimulation and B9 cell proliferation. Gel shift analysis of STAT nuclear factors showed activation of STAT DNA binding in nuclei of B9 cells treated with IgG anti-rat sIL-6R, whereas in H35, NIH-3T3 and M1 cells, only IL-6 could trigger a similar STAT activation. Our data suggest that mechanisms of IL-6 receptor activation and signalling in mouse B9 hybridoma cells show subtle but important differences from other IL-6-responsive cells.
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PMID:Antibodies to rat soluble IL-6 receptor stimulate B9 hybridoma cell proliferation. 918 63

Interleukin-6 (IL-6), a cytokine produced by bone cells, is known to influence bone resorption by stimulating the development of osteoclasts from precursor cells and to have mitogenic actions on osteoblastic cells. Insulin-like growth factors (IGFs) are important local regulators of bone formation, and IGF binding protein (IGFBP)-5 stimulates bone cell growth and enhances the effects of IGF-I. We tested the effects of IL-6 in the presence and absence of its soluble receptor (sIL-6R) on IGFBP-5 expression in cultures of osteoblast-enriched cells from 22-day-old fetal rat calvariae (Ob cells). When tested individually, IL-6 and sIL-6R had a modest stimulatory effect on IGFBP-5 messenger RNA (mRNA) levels. In contrast, when IL-6 and sIL-6R were tested in combination, they caused a considerable increase in IGFBP-5 mRNA levels, and IL-6 at 100 ng/ml and sIL-6R at 125 ng/ml increased IGFBP-5 transcripts by 5- to 7-fold after 24 h. The effect of IL-6 and sIL-6R on IGFBP-5 transcripts was not blocked by indomethacin, but cycloheximide markedly inhibited IGFBP-5 mRNA levels in control and treated cultures. IL-6 and sIL-6R did not modify the decay of IGFBP-5 mRNA in transcriptionally arrested Ob cells, and stimulated the rate of IGFBP-5 transcription as demonstrated by a nuclear run-on assay. IL-6 and sIL-6R did not increase intact IGFBP-5 levels in the extracellular matrix and increased IGFBP-5 fragments in the culture medium. Conditioned medium from Ob cells induced the proteolytic fragmentation of an IGFBP-5 standard, an effect that was accelerated and enhanced by conditioned medium from IL-6/sIL-6R-treated cultures and prevented by metalloprotease inhibitors. In conclusion, IL-6, in the presence of sIL-6R, stimulates IGFBP-5 mRNA expression in Ob cells by transcriptional mechanisms, and accelerates the fragmentation of the protein.
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PMID:Interleukin-6 and its soluble receptor regulate the expression of insulin-like growth factor binding protein-5 in osteoblast cultures. 923 91

Plasma concentrations of interleukin-6 (IL-6) and its soluble receptor (sIL-6R) were serially determined in 32 patients with acute myeloid leukemia who developed severe sepsis (n = 19) or septic shock (n = 13) during chemotherapy-induced leukocytopenia (< or = 1 x 10(9)/L). Starting within 2 h of fever onset, IL-6 levels rose significantly over baseline in both groups to markedly higher levels in patients with evolving septic shock (medians: 372 vs. 3671 pg/mL; P < .001). Simultaneously, sIL-6R significantly decreased to lower levels in shock patients than in septic patients without hypotension (53 vs. 93 ng/mL; P = .02). This pattern was maintained throughout the observation period of up to 6 days. In patients with fatal sepsis, peak IL-6 levels were significantly higher than in survivors (P < .001), whereas minimum sIL-6R levels were markedly lower (P = .003). The reciprocal changes in circulating IL-6 and sIL-6R suggest a role for sIL-6R in modulating the effects of IL-6 during evolving sepsis in leukocytopenic patients.
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PMID:Reciprocal changes in circulating interleukin-6 and its soluble receptor during evolving sepsis in leukocytopenic patients. 929 45

The transmembrane protein gp130 is involved in many cytokine-mediated cellular responses and acts therein as the signal-transducing subunit. In the case of interleukin-6 (IL-6), the signal-transducing complex is composed of the ligand IL-6, the IL-6 receptor (IL-6R, gp80, CD126), and at least two gp130 (CD130) molecules. The extracellular part of the signal transducer gp130 consists of six fibronectin type III-like domains. It has recently been shown that the three membrane distal domains bind to the IL-6. IL-6R complex. A structural model of the IL-6.IL-6R.gp130 complex enabled us to propose amino acid residues in these domains of gp130 interacting with IL-6 bound to its receptor. The proposed amino acid residues located in the B'C' loop (Val252) and in the F'G' loop (Gly306, Lys307) of domain 3 and in the hinge region (Tyr218) connecting domains 2 and 3 of gp130 were mutated to disturb ternary complex formation. Binding of wild type and mutants of the extracellular region of gp130 was studied by use of a co-precipitation assay and Scatchard analysis. All mutants showed decreased binding to the IL-6.IL-6R complex. Biological function of the membrane-bound gp130 mutants was studied by STAT (signal transducer and activator of transcription) activation in COS-7 cells and by proliferation of stably transfected Ba/F3 cells. Reduced binding of the mutants was accompanied by decreased biological activity. The combined approach of molecular modeling and site-directed mutagenesis has led to the identification of amino acid residues in gp130 required for complex formation with IL-6 and its receptor.
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PMID:Molecular modeling-guided mutagenesis of the extracellular part of gp130 leads to the identification of contact sites in the interleukin-6 (IL-6).IL-6 receptor.gp130 complex. 929 19

The cytokines interleukin-2 (IL-2) and interleukin-6 (IL-6) increase during immune activation, they are released from activated astrocytes and microglial cells in the central nervous system (CNS), and they are able to enhance the catecholaminergic neurotransmission. This study focused on the soluble receptors of IL-2 and IL-6 (sIL-2R, sIL-6R) as a part of the regulation system of IL-2 and IL-6. We studied serum levels of sIL-2R in 30 schizophrenic patients not under neuroleptic medication during an acute exacerbation of the disease and reexamined these patients under neuroleptic treatment after clinical improvement. The sIL-6R levels of 39 schizophrenic patients were estimated under the same conditions. The results were compared with the levels of sIL-2R and sIL-6R in 42 healthy controls. No difference was found between the schizophrenic patients before neuroleptic treatment and the healthy controls. During neuroleptic treatment, however, there was a significant increase of sIL-2R levels and a significant decrease of the sIL-6R levels between the pre- and post-conditions. In comparison with healthy controls, the treatment group also showed increased sIL-2R levels and decreased sIL-6R levels. These results suggest that treatment with neuroleptics is associated with increased sIL-2R and decreased sIL-6R. Since sIL-2R bind and inactivate IL-2, whereas sIL-6R form an active complex with IL-6, the increase of sIL-2R and the decrease of sIL-6R together may reflect a functional down regulation of these activating cytokines. This suggests that neuroleptic therapy has a differentiated immunomodulatory effect.
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PMID:Neuroleptic treatment increases soluble IL-2 receptors and decreases soluble IL-6 receptors in schizophrenia. 947 10

Since the discovery a decade ago that interleukin-6 is a growth factor for human multiple myeloma (MM) cells, great strides have been made in understanding the relationship of this cytokine to multiple myeloma. A plethora of studies on this topic has confirmed that interleukin-6 is a key growth and survival factor for myeloma cells, as well as a major morbidity factor for patients with MM. Their is strong evidence for both an autocrine (in MM cells) as well as a paracrine sources of interleukin-6 induction (from bone marrow stromal cells and osteoblast cells), with bone marrow stromal cells likely serving as the main center of production of interleukin-6 in patients with MM. Moreover, bone marrow stromal cells from patients with MM express viral interleukin-6, a functional homolog of human interleukin-6 that is produced by Kaposi's sarcoma-associated herpesvirus and may further enhance MM cell growth and survival. Soluble interleukin-6 receptor serum levels are elevated in patients with MM; soluble interleukin-6 receptor may amplify circulating interleukin-6 in patients with MM, and complex with interleukin-6, resulting in proliferation of MM cells that either express low or no detectable surface interleukin-6 receptor. Recent advances in our understanding of interleukin-6 signaling cascades mediating MM growth and survival, as well as its impact on cell cycle regulation in MM cells, may lead to therapeutics designed to interfere with these pathways. Finally, considerable progress has been made in identifying and developing agents including antibodies, biologic agents, hormones and drugs that interfere with the interleukin-6 signaling pathways and may therefore have a role in the treatment of MM.
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PMID:Interleukin-6 in multiple myeloma and related plasma cell dyscrasias. 951 2

Interleukin-6 (IL-6) on target cells binds to the specific IL-6 receptor (IL-6R) and subsequently induces homodimerization of the signal-transducing protein gp130. Cells which express gp130 but no IL-6R and which therefore do not respond to IL-6 can be stimulated by the complex of IL-6 and soluble IL-6R (slL-6R). Here we show that on rat pheochromocytoma cells (PC12), the combination of IL-6 and slL-6R but not IL-6 alone induces expression of c-fos, GAP-43 and neuron-specific enolase followed by neuron-specific differentiation and formation of a neuronal network. The differentiation was dose-and time-dependent and followed the same kinetics as nerve-growth factor (NGF)-induced differentiation. The responses of PC12 cells to IL-6/sIL-6R and NGF were additive, suggesting independent signaling pathways. We demonstrate that activation of gp130 generates a neuronal differentiation signal that is equivalent to and independent of trk/NGF receptor tyrosine kinase. Interestingly, the failure of IL-6 to induce differentiation of PC12 cells is not due to lack of surface expression of IL-6R as IL-6 alone triggered expression of GAP-43 mRNA and protein. We hypothesize that PC12 cells express more gp130 than IL-6R and that the extent of activated gp130 molecules determines the quality of the response.
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PMID:Activation of gp130 by IL-6/soluble IL-6 receptor induces neuronal differentiation. 951 81

Elevated uterine concentrations of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) are suspected to cause increased prostaglandin release from gestational tissues, but little information is available about the expression pattern of cytokine receptors in these tissues. In this study, cytokine receptor positive cells in frozen tissue sections of placentae (n=70) and fetal membranes (n=50) were identified by immunohistological staining with monoclonal antibodies specific for IL-6 receptor, TNF receptors I and II, and IL-1 receptor I. Both subunits of the IL-6 receptor (gp130 and gp80) as well as TNF receptors I and II were expressed by fetal endothelial cells within placental villi, while IL-1-receptor I was detected exclusively in stromal cells of the maternal decidua. The IL-1 receptor I and TNF receptors I and II were expressed in both uterine quiescence and labour, irrespective of gestational age. Immunoreactivity of the gp130 subunit of the IL-6 receptor was found also throughout pregnancy, while the appearance of the gp80 subunit correlated with the presence of term and preterm labour. In case of preterm labour, expression of the gp80 subunit was predominantly detected in the absence of intrauterine infection. Therefore, it is concluded that the de novo expression of the gp80 subunit and consequently the appearance of entire IL-6 receptors in the placenta is associated with spontaneously occurring labour at term and also with preterm occurring labour in the absence of inrauterine infection.
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PMID:Expression of cytokine receptors in the placenta in term and preterm labour. 954 83

In order to examine which cytokine could be used as a marker of the biological effect of thyroid hormones or anti-thyroid antibodies in Graves' disease (GD) patients, we simultaneously evaluated the concentrations of TSH, free thyroid hormones (fT3 and fT4), anti-thyroid antibodies (anti-TPO and anti-TG) and a group of cytokines: interleukin-2 (IL-2), tumour necrosis factor alpha (TNFalpha), interleukin-6 (IL-6) and their soluble receptors (sIL-2R, sTNFalphaR, sIL-6R) as well as interleukin-10 (IL-10) in eight GD females and nine normal controls. We found that serum sIL-2R concentrations of GD patients had only the tendency to be higher versus controls, but strong positive correlations between fT3 and fT4 and sIL-2R in peripheral blood of GD subjects were revealed. We showed that sIL-2R was the best cytokine marker, showing very good correlation with the endocrine status of GD patients.
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PMID:Cytokines serum levels as the markers of thyroid activation in Graves' disease. 955 56

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

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