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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 (IL-6) exerts its effects by binding to specific receptors on the cell surface. The IL-6 receptor consists of at least two components, a ligand binding 80 kDa low-affinity component (IL-6R) and a signal-transducing non-ligand binding 130 kDa component (gp130). The presence of soluble forms of these components has been described in both conditioned media and biological fluids. The soluble (s) IL-6R has been shown to enhance the IL-6 sensitivity of several both murine and human IL-6 sensitive cell types. A sensitive and commonly used method for measuring biological IL-6 activity is based on the IL-6 dependent proliferation of the murine hybridoma cell line B9. In this paper, we demonstrate that recombinant (r) human (h) sIL-6R enhances the sensitivity of B9 cells in a dose-dependent manner. The rhsIL-6R enhanced the binding of 125I-rhIL-6 to B9 cells. The rhsIL-6R induced stimulation of B9 proliferation was maximal at 100 ng/ml, even without addition of rhIL-6 and in the presence of anti-hIL-6 antibodies. This may be due to endogenous IL-6 production by the B9 cells, low levels of IL-6 in the fetal calf serum used, or perhaps an IL-6 independent effect by the rhsIL-6R. In conclusion, this and other reports point to the necessity of confirming measured biological activities through the use of neutralizing specific antibodies or parallel measurements in immunochemical assays.
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PMID:Stimulation of the B9 hybridoma cell line by soluble interleukin-6 receptors. 804 56

Leukemia inhibitory factor (LIF) is structurally related to interleukin-6 (IL-6), oncostatin M (OSM), and ciliary neurotrophic factor (CNTF). Since LIF-deficient mice do not exhibit overt phenotypic effects in cell types known to be targets for LIF action in vitro, we examined the ability of IL-6, OSM, and CNTF to reproduce the effects of LIF in five different bioassays. OSM, CNTF, and LIF are able to promote embryonic stem cell growth and to maintain them in an undifferentiated state as marked by a high alkaline phosphatase activity (ED50 are, respectively, 0.5, 3 and 1 ng/ml). Whereas LIF and OSM maintain close to 100% of ES cells in an undifferentiated state, CNTF, at optimal concentrations, prevents differentiation of only 60% of the ES population. Murine 7TD1 hybridoma cell growth is induced only in the presence of IL-6 (ED50 = 0.1 ng/ml). Both LIF and OSM stimulate DA1a cell proliferation (ED50 are, respectively, 1 and 12 ng/ml). OSM appears, therefore, to act as a weak agonist of LIF-dependent processes on murine cells, however, with a 10-fold lower specific activity than that of LIF, which is in agreement with human OSM cross-reacting with the murine LIF-R. Though IL-6, LIF, and OSM all stimulate haptoglobin and fibrinogen production by human HepG2 hepatoma cells, the dose-response curves of these three factors exhibit very different characteristics. CNTF stimulates acute-phase protein production by HepG2 cells only at high concentrations (greater than 1 microgram/ml). A549 epithelial cells are subjected to growth inhibition only in the presence of OSM (ED50 = 6 ng/ml), even though they expressed LIF-R and gp130 transcripts. These data suggest that OSM and LIF act on human cells through different receptors. Altogether, these results indicate that none of the factors examined in this study are precisely interchangeable in terms of their biological actions.
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PMID:Are LIF and related cytokines functionally equivalent? 805 Apr 91

The human interleukin-6 receptor (IL-6R) was differentially expressed on IL-6-dependent (U266 and SKO-007) and -independent (RPMI8226) myeloma cells as well as melanoma cells (A375-C6) that are growth-inhibited by IL-6. U266 and SKO-007 cells expressed four distinct IL-6R complexes (molecular masses of 100, 120, 145, and 165 kDa) as revealed by affinity cross-linking of iodinated IL-6. RPMI8226 and A375-C6 cells primarily expressed the 165-kDa complex relative to the others. Immunoprecipitation and antibody competition studies showed that the 100- and 120-kDa complexes contained the gp80 subunit, whereas the 145- and 165-kDa complexes contained the gp130 subunit of the IL-6R. Assaying solubilized U266 plasma membrane proteins by affinity cross-linking or ligand blotting revealed that only gp80 bound IL-6 specifically. Induction of an IL-6 response was associated with ligand-induced down-regulation of gp130 and was inhibited by neutralizing anti-IL-6 antibodies. Furthermore, the relative ratios of gp80 to gp130 determined the binding kinetics of the IL-6R, yielding high- and low-affinity binding sites by Scatchard plots. Our data imply that distinct IL-6 bioactivities are based upon the differential expression and regulation by IL-6 of its ligand-binding (gp80) and signal-transducing (gp130) receptor subunits.
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PMID:Differential expression and ligand-induced modulation of the human interleukin-6 receptor on interleukin-6-responsive cells. 812 32

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates various aspects of the immune response, acute-phase reaction and haematopoiesis (for reviews see refs 1, 2). In vitro, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and interleukin-11 display overlapping activities with IL-6. This functional redundancy may be explained by the interactions of specific binding receptors with a common signal-transducing receptor (gp130) (for reviews see refs 3, 4). To elucidate the unique function of IL-6 in vivo, we have disrupted the IL-6 gene by homologous recombination. IL-6-deficient mice develop normally. They fail to control efficiently vaccinia virus and infection with Listeria monocytogenes, a facultative intracellular bacterium. The T-cell-dependent antibody response against vesicular stomatitis virus is impaired. Further, the inflammatory acute-phase response after tissue damage or infection is severely compromised, whereas it is only moderately affected after challenge with lipopolysaccharide. We conclude that IL-6 production induced by injury or infection is an important in vivo SOS signal which coordinates activities of liver cells, macrophages and lymphocytes.
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PMID:Impaired immune and acute-phase responses in interleukin-6-deficient mice. 812 68

Interleukin-6, leukemia inhibitory factor, and oncostatin M exert a broad range of similar biological activities through association of their receptors with the signal-transducing component gp130. Although it is known that these cytokines trigger rapid tyrosine phosphorylation of a common set of cellular proteins as well as induction of several of the same early response genes, the mechanisms by which these genes are activated is not well understood. In this report, we show that interleukin-6, leukemia inhibitory factor, and oncostatin M stimulate the assembly of protein complexes that recognize conserved sequences within the enhancers of two genes (interferon regulatory factor 1 and Fc gamma receptor type I) that are rapidly activated by these cytokines. These enhancers are known to be required for transcriptional induction of these genes by interferon-gamma. Assembly of the DNA-binding protein complexes occurs within minutes after ligand addition and depends upon tyrosine phosphorylation. These complexes contain the p91 transcription factor, which is tyrosine-phosphorylated in response to these cytokines. An additional tyrosine-phosphorylated protein of 93 kDa can be coimmunoprecipitated with antibodies against p91. These findings further expand the network of cytokines known to activate p91 and, in addition, support the concept that sets of tyrosine-phosphorylated proteins may be responsible for the cytokine-regulated expression of early response genes.
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PMID:Cytokines that associate with the signal transducer gp130 activate the interferon-induced transcription factor p91 by tyrosine phosphorylation. 814 63

Interleukin-6 (IL-6), leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotropic factor are a family of cytokines and neuronal differentiation factors which bind to composite plasma membrane receptors sharing the signal transducing subunit gp130. We have shown recently that IL-6 and leukemia inhibitory factor rapidly activate a latent cytoplasmic transcription factor, acute-phase response factor (APRF), by tyrosine phosphorylation, which then binds to IL-6 response elements of various IL-6 target genes. Here we demonstrate that APRF is activated by all cytokines acting through gp130 and is detected in a wide variety of cell types, indicating a central role of this transcription factor in gp130-mediated signaling. APRF activation is also observed in vitro upon addition of IL-6 to cell homogenates. Protein tyrosine kinase inhibitors block both the tyrosine phosphorylation and DNA binding of APRF. The factor was purified to homogeneity from rat liver and shown to consist of a single 87-kDa polypeptide, while two forms (89 and 87 kDa) are isolated from human hepatoma cells. As reported earlier, the binding sequence specificity of APRF is shared by gamma interferon (IFN-gamma) activation factor, which is formed by the Stat91 protein. Partial amino acid sequence obtained from purified rat APRF demonstrated that it is likely to be related to Stat91. In fact, an antiserum raised against the amino-terminal portion of Stat91 cross-reacted with APRF, suggesting the relatedness of APRF and Stat91. Altogether, these data indicate that APRF belongs to a growing family of Stat-related proteins and that IFN-gamma and IL-6 use similar signaling pathways to activate IFN-gamma activation factor and APRF, respectively.
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PMID:The interleukin-6-activated acute-phase response factor is antigenically and functionally related to members of the signal transducer and activator of transcription (STAT) family. 816 74

Interleukin-6 (IL-6) is a multifunctional cytokine playing various roles in the immune system, hematopoiesis and acute phase reactions. To elucidate the intracellular signal transduction mechanism through the IL-6 receptor, we investigated IL-6-induced protein tyrosine phosphorylation in murine hematopoietic cell lines, BAFm130 and Y6. IL-6 stimulated tyrosine phosphorylation of multiple cellular proteins, such as gp130, an IL-6 signal transducer; Jak family of the cytoplasmic tyrosine kinases; and the latent cytoplasmic signal transducer and activator of transcription. We showed that the pattern of these tyrosine-phosphorylated molecules was different between BAFm130 and Y6 cells on which IL-6 exhibited different biological activities.
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PMID:Interleukin-6-induced tyrosine phosphorylation of multiple proteins in murine hematopoietic lineage cells. 817 17

Propagation of the undifferentiated pluripotential phenotype of embryonic stem (ES) cells is dependent on the cytokine differentiation inhibiting activity/leukemia inhibitory factor (DIA/LIF). The DIA/LIF receptor complex is a heterodimer of DIA/LIF receptor (DIA/LIF-R) and gp130. The latter is also a component of the interleukin-6 (IL-6) receptor complex. We report that a combination of IL-6 and soluble IL-6 receptor (sIL-6R), which can induce homodimerisation of gp130 and activation of signalling processes, sustains self-renewal of pluripotential ES cells. Our findings indicate that the IL-6/sIL-6R complex acts on ES cells through gp130 alone, bypassing DIA/LIF-R, and therefore implicate gp130 as the key component in the signalling pathway responsible for stem cell renewal.
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PMID:Maintenance of the pluripotential phenotype of embryonic stem cells through direct activation of gp130 signalling pathways. 819 53

We have studied the expression and regulation of the interleukin-6 receptor (gp80) and its signal transducer gp130 in primary human blood monocytes. Here, we show that freshly isolated human monocytes express mRNAs for gp80 and gp130. In contrast to a previous report [(1989) FEBS Lett. 249, 27-30] we find that neither lipopolysaccharide nor interleukin-6 (IL-6) lead to a down-regulation of IL-6 receptor mRNA in monocytes. Also in the human monocytic cell line Mono Mac 6 no effect of IL-6 on receptor mRNA levels was observed. For signal transducer gp130 mRNA in monocytes a small and transient up-regulation by IL-6 was found.
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PMID:Regulation of interleukin-6 receptor expression by interleukin-6 in human monocytes--a re-examination. 820 Apr 44

Leukemia inhibitory factor (LIF) is a polyfunctional molecule with significant and diverse biological activities. LIF is a glycoprotein secreted by a number of different cell types in vitro. It is induced in fibroblasts, lymphocytes, monocytes and astrocytes by various inducers such as serum, TNF, interleukin-IP and EGF. Due to extensive and variable glycosylation the molecular weight can range from 38 to 67 kDA. The biological functions of LIF are mediated through a receptor and a signal transducer, gp130, which is also used by factors like interleukin-6 (IL-6), cilliary neurotropic factor (CNTF), and oncostatin M (OSM). Here, we report the crystallization of the non-glycosylated human-like LIF expressed in E. coli. The present crystals diffract to 2.0 A using synchrotron radiation. They belong to the monoclinic space group C2, and the cell dimensions are a = 61.5 A, b = 45.3 A, c = 77.7 A and beta = 112.3 degrees.
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PMID:Crystallization and preliminary X-ray analysis of leukemia inhibitory factor. 826 36


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