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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 (IL6) exerts its action via a cell surface receptor composed of an 80 kDa IL6-binding protein (gp80) and a 130 kDa polypeptide involved in signal transduction (gp130). We studied the role of gp80 in binding, internalization and down-regulation of the hepatic IL6-receptor (IL6R) by its ligand in human hepatoma cells (HepG2). Comparison of transfected HepG2 cells overexpressing gp80 with parental cells indicate that gp80 is responsible for low affinity binding (Kd = 500 pM) of IL6. Furthermore, gp80 is rate-limiting in internalization and degradation of IL6. Internalization resulted in a rapid down-regulation (t1/2 approximately 15-30 min) of IL6-binding sites at the cell surface. More than 80% of the internalized [125I]rhIL6 was degraded. The reappearance of IL6-binding sites at the cell surface required greater than 8 h and was sensitive to cycloheximide, suggesting that gp80 is not recycled after internalization. The down-regulation of the hepatic IL6R by its ligand might play an important role as a protection against overstimulation.
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PMID:The hepatic interleukin-6 receptor. Down-regulation of the interleukin-6 binding subunit (gp80) by its ligand. 132 36

Interleukin-6 (IL-6) induces changes in gene expression and the N-glycosylation pattern of acute-phase proteins in hepatocytes. IL-6 exerts its action via a cell surface receptor complex consisting of an 80 kDa IL-6 binding protein (gp80) and a 130 kDa glycoprotein (gp130) involved in signal transduction. A genetically engineered gp80-derived soluble human IL-6-receptor (shIL-6-R) significantly enhanced the IL-6 effect on N-glycosylation changes (revealed by reactivity with the lectin-concanavalin A) of a1-protease inhibitor (PI) secreted by human hepatoma cells (HepG2). Stable transfection of IL-6-cDNA into HepG2 cells (HepG2-IL-6) resulting in constitutive secretion of 2 micrograms of IL-6 per 10(6) cells in 24 h led to a down-regulation of surface-bound gp80 and subsequent homologous desensitization of HepG2-IL-6 cells towards IL-6. Soluble human IL-6-R functionally substituted membrane-bound gp80 resulting in a reconstitution of responsiveness of HepG2-IL-6 cells.
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PMID:Soluble human interleukin-6-receptor modulates interleukin-6-dependent N-glycosylation of alpha 1-protease inhibitor secreted by HepG2 cells. 132 38

We previously found that the level of Fas, a cell surface receptor for an apoptosis signal, increases at the mRNA level in influenza virus-infected HeLa cells prior to their death by apoptosis. Here we investigated the mechanism of activation of the Fas-encoding gene expression upon influenza virus infection. Nucleotide sequences for the binding of nuclear factor for interleukin-6 expression (NF-IL6), also known as CCAAT/enhancer-binding protein beta, were repeated 8 times in the 5'-end region of the human FAS gene, spanning from -1360 to +320. This region directed the expression of a downstream marker gene when introduced into HeLa cells and the activity of the FAS gene promoter was stimulated about 2-fold upon influenza virus infection. Gene expression driven by the FAS promoter was activated when human NF-IL6 was overproduced in a DNA when human NF-IL6 was overproduced in a DNA co-transfection study. Moreover, the DNA-binding activity of NF-IL6 increased after infection with the virus, whereas the amount of NF-IL6 seemed unchanged. The results suggest that NF-IL6 is activated upon influenza virus infection through post-translational modification and that the modified factor stimulates the transcription of the human FAS gene.
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PMID:Transcription stimulation of the Fas-encoding gene by nuclear factor for interleukin-6 expression upon influenza virus infection. 754 95

The mechanism by which the binding of growth hormone (GH) to its cell surface receptor elicits changes in gene transcription are largely unknown. The transcription factor Stat1/p91 has been shown to be activated by GH. Here we show that acute phase response factor or Stat3 f1p4an antigenically related protein), is also activated by GH. Stat3 has been implicated in the interleukin-6-dependent induction of acute phase response genes. GH promotes in 3T3-F442A fibroblasts the tyrosyl phosphorylation of a protein immunoprecipitated by antibodies to Stat3. This protein co-migrates with a tyrosyl phosphorylated protein from cells treated with leukemia inhibitory factor, a cytokine known to activate Stat3. Tyrosyl phosphorylated Stat3 is also observed in response to interferon-gamma. Stat3 is present in GH-inducible DNA-binding complexes that bind the sis-inducible element in the c-fos promoter and the acute phase response element in the alpha 2-macroglobulin promoter. The ability of GH to activate both Stat1 and Stat3 (i.e. increase their tyrosyl phosphorylation and ability to bind to DNA) suggests that gene regulation by GH involves multiple Stat proteins. Shared transcription factors among hormones and cytokines that activate JAK kinases provide an explanation for shared responses, while the ability of the different ligands to differentially recruit various Stat family members suggests mechanisms by which specificity in gene regulation could be achieved.
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PMID:Activation of acute phase response factor (APRF)/Stat3 transcription factor by growth hormone. 787 44

Interleukin-6 (IL-6) exerts its action via a cell surface receptor complex consisting of two subunits, the IL-6 receptor and the signal transducer gp130. We have studied the role of both transmembrane proteins for IL-6 internalization and ligand-induced down-regulation of cell surface receptors. Co-expression of wild-type and mutant forms of both the IL-6 receptor and gp130 in transiently transfected COS-7 cells revealed that gp130 is essential for efficient endocytosis and receptor down-regulation. Whereas the cytoplasmic domain of the IL-6 receptor is not significantly involved in the internalization process, deletion of the corresponding domain of gp130 resulted in an almost complete loss of the ability to endocytose IL-6. Mutants with different truncations within the intracellular domain of gp130 revealed that a 10-amino acid sequence TQPLLDSEER is crucial for efficient internalization. Since this sequence contains a putative di-leucine internalization motif, we suggest that a di-leucine motif directs the receptor mediated endocytosis of the IL-6 receptor complex.
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PMID:Identification of a region within the cytoplasmic domain of the interleukin-6 (IL-6) signal transducer gp130 important for ligand-induced endocytosis of the IL-6 receptor. 803 58

Neoplastic diseases are frequently associated with metabolic changes collectively known as cancer cachexia. The presence of cachexia complicates therapeutic intervention and is an important cause of death in cancer patients. At present there is no effective treatment for cachexia. Recently, the involvement of interleukin-6 (IL-6) in the wasting of colon-26 adenocarcinoma-bearing mice was demonstrated. The research presented here establishes an anticachectic role for the experimental drug suramin, since it partially blocks (up to 60%) the catabolic effects associated with the growth of this tumor in vivo. Suramin prevents the binding of IL-6 to its cell surface receptor subunits, as demonstrated by radioreceptor binding assay and affinity crosslinking experiments. Furthermore, the uptake of radioactive IL-6 by the liver is significantly reduced in suramin-treated mice. On the other hand, the drug is approximately 10-fold less potent in inhibiting the binding of tumor necrosis factor-alpha to indicator cell line in vitro and fails to block liver uptake of this cytokine in vivo. Collectively, these results suggest that suramin inhibits cancer-associated wasting, in part by interfering with the binding of IL-6 to its receptor. Whether suramin inhibits the action of other factors/cytokines that may also participate in colon-26-mediated cachexia is not yet known.
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PMID:Suramin interferes with interleukin-6 receptor binding in vitro and inhibits colon-26-mediated experimental cancer cachexia in vivo. 822 30

Interferon-gamma (IFNgamma) transmits its signal through a specific cell surface receptor (IFNgammaR), which consists of a primary ligand binding alpha-chain (IFNgammaR alpha) and a signaling beta-chain (IFNgammaR beta). Recent studies identified the cytokines IFNgamma, interleukin-6 (IL-6), IL-1alpha, and tumor necrosis factor-alpha in testicular cells. Therefore, we: 1) examined the expression of IFNgammaR alpha and IFNgammaR beta subunits in freshly isolated and purified rat testicular cells; 2) examined the differential regulation of receptor components by cytokines using primary cultures of Sertoli cells; 3) identified the cell signaling pathway components of testicular IFNgammaR; and 4) characterized the functional role of testicular IFNgamma using primary Sertoli cells. We demonstrated the messenger RNAs for both chains of IFNgammaR in rat testicular cells using Northern hybridization analysis. Western blot analysis and immunocytochemistry showed that both specific IFNgammaR protein subunits were present in cultured primary Leydig and Sertoli cells prepared from the testes of immature rats. The expression of both IFNgammaR component messenger RNAs in cultured Sertoli cells was increased by its specific ligand (IFNgamma), as well as IL-1alpha and tumor necrosis factor-alpha, in both a time- and dose-dependent manner. IFNgamma-activation of the Janus (JAK) tyrosine kinases, JAK1 and JAK2 proteins, indicate that IFNgammaR, expressed in the Sertoli cell, is functional. Moreover, IFNgamma modulates the expression of interferon regulatory factor (IRF)-1 and IL-1beta converting enzyme genes in Sertoli cells. Thus, our data are suggestive of a role(s) for IFN-gamma in the regulation of distinct gene expression and cell-specific sensitivity to apoptosis in the testis.
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PMID:Identification and regulation of testicular interferon-gamma (IFNgamma) receptor subunits: IFNgamma enhances interferon regulatory factor-1 and interleukin-1beta converting enzyme expression. 956 81

In the standard model of cytokine-induced signal transducer and activator of transcription (STAT) protein family signaling to the cell nucleus, it is assumed that STAT3 is recruited to the cytoplasmic side of the cell surface receptor complex from within a cytosolic monomer pool. By using Superose-6 gel-filtration chromatography, we have discovered that there is little monomeric STAT3 (91 kDa) in the cytosol of liver cells (human hepatoma Hep3B cell line and rat liver). The bulk of STAT3 (and STAT1, STAT5a, and -b) was present in the cytosol as high molecular mass complexes in two broad distributions in the size range 200-400 kDa ("statosome I") and 1-2 MDa ("statosome II"). Upon treatment of Hep3B cells with interleukin-6 (IL-6) for 30 min (i) cytosolic tyrosine-phosphorylated STAT3 was found to be in complexes of size ranging from 200-400 kDa to 1-2 MDa; (ii) a small pool of monomeric STAT3 and tyrosine-phosphorylated STAT3 eluting at 80-100 kDa was observed, and (iii) most of the cytoplasmic DNA-binding competent STAT3 (the so-called SIF-A "homodimer") co-eluted with catalase at 230 kDa. In order to identify the protein components of the 200-400-kDa statosome I cytosolic complexes, we used the novel technique of antibody-subtracted differential protein display using anti-STAT3 antibody. Eight polypeptides in the size range from 20 to 114 kDa co-shifted with STAT3; three of these (p60, p20a, and p20b) were co-shifted in an IL-6-dependent manner. In-gel tryptic fragmentation and mass spectroscopy identified the major IL-6-dependent STAT3-co-shifted p60 protein as the chaperone GRP58/ER-60/ERp57. Taken together, these data (i) emphasize the absence of a detectable STAT3 monomer pool in the cytosol of cytokine-free liver cells as posited by the standard model, and (ii) suggest an alternative model for STAT signaling in which STAT3 proteins function in the cytoplasm as heteromeric complexes with accessory scaffolding proteins, including the chaperone GRP58.
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PMID:Cellular physiology of STAT3: Where's the cytoplasmic monomer? 1046 81

CD40 is a cell surface receptor initially discovered on cells of the hemopoietic lineage. Its primary role on immune cells is to enhance their activation and hence their production of cytokines and immunomodulatory molecules. Recently, CD40 has also been detected on human fibroblasts. An emerging view of the fibroblast is that it is far more than a structural cell, being capable of intimate interaction with cells of the immune system. In fibroblasts from several tissues, the engagement of CD40 with its ligand (CD40L) resulted in the secretion of proinflammatory molecules such as interleukin-6 (IL-6) and IL-8. Currently, there are few data about the presence of the CD40-CD40L system in female reproductive tissues. This study investigates the expression of CD40 by human endometrium, myometrium, and cervix both in situ and in tissue explant-derived fibroblasts. CD40 was detected mainly in the perivascular region of endometrium, myometrium, and cervix. Light staining for CD40 was observed in stromal elements. Additionally, the basal epithelium of cervix expressed CD40. Fibroblastic cells derived from all three sources express low levels of CD40, and this is up-regulated with interferon-gamma treatment (500 U/mL; 72 h). When activated with interferon-gamma and CD40L, the fibroblasts secreted increased amounts of IL-6, IL-8, and MCP-1. These data suggest that the CD40-CD40L system may provide a link between the resident structural cells of these reproductive tissues and the infiltrating immune cells or activated platelets that may express CD40L. The possible interaction of CD40 with CD40L may be particularly important during events such as menstruation and cervical ripening, where up-regulation of the proinflammatory molecules IL-6 and IL-8 is viewed as critical for these processes. In addition, dysregulation of this system may be a contributory factor to problems such as menstrual dysfunction and preterm labor.
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PMID:Cd40 expression in uterine tissues: a key regulator of cytokine expression by fibroblasts. 1123 32

Angiogenesis plays an important role in multiple myeloma (MM) progression. Various mitogens such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF-2) have been implicated in the angiogenic process of various malignancies. Interleukin-6 (IL-6) is a growth factor of myeloma cells and its signaling is mediated via a cell surface receptor complex (IL-6r). IL-6 and tumor necrosis factor-alpha (TNF-alpha) are involved in the secretion of VEGF by IL-6r expressing myeloma cells. In this study, serum FGF-2, VEGF, IL-6r, and TNF-alpha were measured in 46 untreated MM patients and were studied in relation to disease stage (by Salmon-Durie criteria) and severity [assessed by serum beta(2)-microglobulin (beta(2)M), C-reactive protein (CRP), alpha(1)-antitrypsin (alpha(1)AT), and lactic dehydrogenase (LDH) levels]. The results showed that FGF-2, VEGF, IL-6r, and TNF-alpha were significantly elevated in MM patients in comparison to controls ( p<0.008) and were significantly higher in stage III disease in comparison to stages I and II ( p<0.03). The mean concentrations of IL-6r were 877+/-374, 1220+/-308, 1431+/-878, and 453+/-180 pg/ml for stages I, II, and III and controls, respectively. Levels of beta(2)M, alpha(1)AT, CRP, and LDH were all significantly higher in MM patients than controls and increased with advancing stage of disease. There were positive correlations of both VEGF and FGF-2 with IL-6r, TNF-alpha, beta(2)M, alpha(1)AT, CRP, and LDH. We conclude that IL-6r and TNF-alpha increase in parallel to VEGF and FGF-2 with increasing stage of MM disease. These molecules correlate with biochemical markers of disease activity and may play a role in the progression of multiple myeloma.
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PMID:Relationship between circulating serum soluble interleukin-6 receptor and the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in multiple myeloma. 1257 59


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