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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Receptors for many of the cytokines functioning in the haematopoietic system belong to the class I cytokine receptor family. In most cases these receptors share common signal transducing receptor components in the same family, which explains the functional redundancy of haematopoietic cytokines. Interleukin-6 and related cytokines, interleukin-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1, are all pleiotrophic, from the haematopoietic to the nervous system, and exhibit overlapping biological activities. Receptors for these cytokines fall into the class I cytokine receptor family. Functional receptor complexes for the interleukin-6 family of cytokines share a membrane glycoprotein 130 (gp130) as a critical component for signal transduction. In these receptor complexes, gp130 and ligand-specific chains possess no intrinsic tyrosine kinase domain but are associated with cytoplasmic tyrosine kinases. Ligand stimulation triggers homo- or heterodimerization of gp130, leading to activation of the associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews the recent progress in the study of gp130 and the background information from biomedical and biochemical viewpoints.
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PMID:The signal transducer gp130 is shared by interleukin-6 family of haematopoietic and neurotrophic cytokines. 907 25

Proinflammatory cytokines, tumor necrosis factor-alpha (TNF alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6), produced by glial cells have been implicated in the neuropathogenesis of various diseases. However, the signal transduction pathway(s) for the production of these cytokines in glial cells are not well understood. This study examined the effects of two potent protein tyrosine kinase inhibitors, genistein and tyrphostin A25, on lipopolysaccharide (LPS)-induced production of TNF alpha, IL-1 alpha, and IL-6 in mouse primary mixed glia, microglia- or astrocyte-enriched cultures. LPS dose-dependently increased the production of TNF alpha, IL-1 alpha, and IL-6 from the mixed glia cultures. Genistein or tyrphostin A25 significantly inhibited the LPS-induced production of these cytokines. The LPS-induced TNF alpha, IL-1 alpha, and IL-6 production in microglia- or astrocyte-enriched cultures were also inhibited by tyrphostin A25. These results demonstrate that protein tyrosine kinases are involved in the signaling events of the LPS-induced production of TNF alpha, IL-1 alpha, or IL-6 in microglia or astrocytes, which may provide insights into therapeutic interventions in the pathway for cytokine production in the brain.
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PMID:Protein tyrosine kinase inhibitors decrease lipopolysaccharide-induced proinflammatory cytokine production in mixed glia, microglia-enriched or astrocyte-enriched cultures. 910 65

Interleukin-6 (IL-6) inhibitors are good potential therapeutic agents in human patients, and anti-IL-6 antibodies are among the best candidates. Here, we have successfully humanized mouse monoclonal antibody SK2, which specifically binds to IL-6 and strongly inhibits IL-6 functions. Since this antibody possesses N-linked carbohydrates on Asn-30 of VH region, which seems to be very close to an antigen-binding site, influence of these carbohydrates on antigen-binding was investigated. A biosensor study showed that the mouse SK2 Fab and its deglycosylated fragments had almost equal Kd (Kon/Koff), 26.8 nM (1.05 x 10(6)/2.81 x 10(-2)) and 24.7 nM (1.28 x 10(6)/3.15 x 10(-2)), respectively. Furthermore, a mutant chimeric SK2 antibody, in which the N-glycosylation site was removed from the VH region, showed a Kd of 11 nM, almost similar to that of the original chimeric SK2 antibody, determined by Scatchard analysis with 125I-IL-6. These data indicate the carbohydrates of mouse SK2 VH region do not significantly influence antigen-binding activity. In the next step, two versions of each humanized SK2 VL and VH regions were carefully designed based on the amino acid sequences of human REI and DAW, respectively. Only one alteration, Tyr to Phe, was made at position 71 in the two light chains, according to the canonical residue for LI. A N-glycosylation site was introduced on the two heavy chains, by changing Ser to Asn at position 30. All four combinations of humanized light and heavy chains could bind to IL-6 as well as the chimeric SK2 antibody. The light chain first version, however, could not efficiently inhibit IL-6 binding to its receptor, indicating the importance of the LI loop conformation for the inhibitory activity of SK2 antibody. In contrast, both versions of the heavy chains were comparable, in yielding good humanized SK2 antibodies, suggesting that the glycosylation of the SK2 VH region has no influence in recreating a functional antigen-binding site in this humanization.
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PMID:Humanization of an anti-human IL-6 mouse monoclonal antibody glycosylated in its heavy chain variable region. 914 Jul 29

Receptors for most interleukins and cytokines that regulate immune and hematopoietic systems belong to the class I cytokine receptor family. These molecules form multichain receptor complexes in order to exhibit high-affinity binding to, and mediate biological functions of, their respective cytokines. In most cases, these functional receptor complexes share common signal transducing receptor components that are also in the class I cytokine receptor family, i.e. gp130, common beta, and common gamma molecules. Interleukin-6 and related cytokines, interleukin-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin-1 are all pleiotropic and exhibit overlapping biological functions. Functional receptor complexes for this interleukin-6 family of cytokines share gp130 as a component critical for signal transduction. Unlike cytokines sharing common beta and common gamma chains that mainly function in hematopoietic and lymphoid cell systems, the interleukin-6 family of cytokines function extensively outside these systems as well, e.g. from the cardiovascular to the nervous system, owing to ubiquitously expressed gp130. Stimulation of cells with the interleukin-6 family of cytokines triggers homo- or hetero-dimerization of gp130. Although gp130 and its dimer partners possess no intrinsic tyrosine kinase domain, the dimerization of gp130 leads to activation of associated cytoplasmic tyrosine kinases and subsequent modification of transcription factors. This paper reviews recent progress in the study of the interleukin-6 family of cytokines and gp130.
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PMID:Gp130 and the interleukin-6 family of cytokines. 914 7

Ciliary neurotrophic factor and an avian homolog, growth promoting activity, are members of the cytokine/neurokine family of trophic factors and have been proposed to function as survival and developmental factors for ciliary ganglion neurons in vivo. Here we identify for the first time functional receptors for ciliary neurotrophic factor and growth promoting activity on cultured ciliary ganglion neurons. [(125)I]Rat ciliary neurotrophic factor binding studies indicate that rat ciliary neurotrophic factor and growth promoting activity bind to these receptors with a single affinity, while human ciliary neurotrophic factor recognizes both a high- and low-affinity site. Comparison of the relative potency of human ciliary neurotrophic factor and avian growth promoting activity in biological assays indicates that growth promoting activity is three to five times more active in promoting survival and in regulating acetylcholine receptors. The binding of ciliary neurotrophic factor is specific, sensitive to phosphatidylinositol-specific phospholipase C and partially inhibited by leukemia inhibitory factor, but not inhibited by other members of the human neurokine family, including interleukin-6, interleukin-22 and oncostatin M. Cross-linking of [(125)I]rat ciliary neurotrophic factor to ciliary neurons results in the specific labeling of three proteins with estimated molecular masses of 153,000, 81,000 and 72,000. Only the 81,000 molecular weight component is released from the cells after treatment with phosphatidylinositol-specific phospholipase C, suggesting a membrane attachment via a glycosylphosphatidylinositol linkage. Stimulation with ciliary neurotrophic factor or growth promoting activity, but not by other neurokines, results in the rapid tyrosine phosphorylation of a 90,000 molecular weight protein that is inhibited by pretreatment with phosphatidylinositol-specific phospholipase C. In conclusion, we report here the pharmacological and functional properties of ciliary neurotrophic factor receptors on embryonic ciliary ganglion neurons. These results provide the means for elaborating the molecular mechanisms of ciliary neurotrophic factor action and understanding its physiological role in a defined neuronal population.
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PMID:Identification of functional receptors for ciliary neurotrophic factor on chick ciliary ganglion neurons. 915 28

We have recently demonstrated that the proinflammatory cytokine, interleukin-6 (IL-6), could upregulate the production of protein S in the human hepatoma cell line, HepG-2, but not in endothelial cells. In this study, we have demonstrated that the combination of exogenous IL-6 and soluble IL-6 receptor (sIL-6R) could significantly upregulate protein S production in both primary human umbilical vein endothelial cells (HUVEC) and in the immortalized human microvascular endothelial cell line, HMEC-1. The IL-6/sIL-6R complex was also able to rapidly induce tyrosine phosphorylation of the IL-6 transducer, gp130. Neutralizing antibodies directed against either IL-6 or gp130 blocked protein S upregulation by the IL-6/sIL-6R complex. It was also observed that exogenous sIL-6R could also upregulate protein S by forming a complex with IL-6 constitutively produced by the endothelial cell. Two other cytokines which also utilize the gp130 receptor, oncostatin M (OSM) and leukemia inhibitory factor (LIF), were also able to upregulate endothelial cell protein S. This study demonstrates a mechanism that allows endothelial cells to respond to IL-6 and also illustrates the potential importance of circulating soluble receptors in the regulation of the anticoagulation pathway.
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PMID:Endothelial cell protein S synthesis is upregulated by the complex of IL-6 and soluble IL-6 receptor. 918 20

Cytokines are secreted proteins that regulate important cellular responses such as proliferation and differentiation. Key events in cytokine signal transduction are well defined: cytokines induce receptor aggregation, leading to activation of members of the JAK family of cytoplasmic tyrosine kinases. In turn, members of the STAT family of transcription factors are phosphorylated, dimerize and increase the transcription of genes with STAT recognition sites in their promoters. Less is known of how cytokine signal transduction is switched off. We have cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. We have also cloned two relatives of SOCS-1, named SOCS-2 and SOCS-3, which together with the previously described CIS form a new family of proteins. Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.
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PMID:A family of cytokine-inducible inhibitors of signalling. 920 25

Leukemia inhibitory factor (LIF) is a cytokine that plays an important role during mouse embryogenesis. We showed that adenovirus E1A represses the interleukin-6 signal transduction pathway that uses the same JAK tyrosine kinase and STAT (signal transducer and activator of transcription) transcription factor as LIF. Here, we report that the LIF-JAK-STAT signal transduction pathway is blocked in cellular E1A-expressing undifferentiated F9 cells, and that the block is overcome by retinoic acid-induced differentiation. LIF failed to stimulate the expression of the acute phase response element (APRE)-driven luciferase gene in undifferentiated F9 cells, whereas the luciferase activity was remarkably increased by LIF treatment in differentiated F9 (dF9) cells. We analyzed the mechanism of the APRE regulation and found that the LIF-induced APRE-binding activity was regulated in a differentiation-dependent manner. The protein levels and the tyrosine phosphorylation of JAK1, JAK2, and STAT3 in F9 cells were not different from those in dF9 cells. The exogenous expression of activated c-Ha-ras partially recovered the LIF responsiveness of the APRE-luciferase gene in F9 cells, but the dominant negative ras N-17 did not repress the LIF-induced activation of APRE-luciferase in dF9 cells. These results suggested that an unknown coactivation process that is partially compensated by Ras is required for STAT3-APRE binding in F9 cells.
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PMID:Alternative signaling mechanism of leukemia inhibitory factor responsiveness in a differentiating embryonal carcinoma cell. 920 5

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

Tyrosine kinases are involved in the phosphorylation of proteins that regulate cell growth and proliferation. The mitogenic effect of several growth factors requires tyrosine kinase activity of their receptors. The effect of inhibition of tyrosine kinase activity on thymidine uptake into cultured human pituitary adenoma cells was studied using two inhibitors, genestein and methyl-2,3-dihydroxycinnamate (MDHC). Of 33 pituitary adenomas, 7 incorporated sufficient [3H]thymidine to be investigated in the experiments. Genestein and MDHC both potently inhibited thymidine uptake into these tumors, with a mean inhibition by 74 mumol/L genestein of 61.96 +/- 18.96% (+/- SD inhibition of basal), by 740 mumol/L genestein of 92.65 +/- 8.59%, and by 100 mumol/L MDHC of 93.84 +/- 3.85%. The 7 pituitary adenomas were all large with suprasellar extension and secreted interleukin-6 in vitro. They included 2 prolactinomas, 1 somatotropinoma, 1 mammosomatropinoma, and 3 clinically nonfunctioning adenomas. Epidermal growth factor stimulated thymidine uptake in 2 of the 3 clinically nonfunctioning adenomas studied, and this stimulation was inhibited by genestein. Both of these tumors released FSH in cell culture and are probably silent gonadotropinomas. The growth stimulatory effect of conditioned medium from human pituitary cell culture on GH3 cells was inhibited by both genestein and MDHC. We conclude that tyrosine kinase activity is crucial for the integrity and growth of pituitary adenomas in culture. Growth factors released by pituitary adenomas potentially may maintain and promote tumor growth by stimulating tyrosine kinase activity.
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PMID:Suppression of tyrosine kinase activity inhibits [3H]thymidine uptake in cultured human pituitary tumor cells. 921 85


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