Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A new myeloma cell line designated FLAM-76 was established from a patient with an aggressive nonsecretory plasma cell leukemia. The cell line exhibited morphologic features of flaming cells and contained an abundant eosinophilic cytoplasm with many dilated cisternae of rough endoplasmic reticulum. FLAM-76 cells were positive for cytoplasmic kappa (kapp)-type immunoglobulin but did not secrete it into the culture medium. The cells proliferated in the presence of exogenous interleukin-6 (IL-6) and more than 800 pg/ml of IL-6 was necessary for their continuous growth. The cells did not grow without IL-6, and they did not produce IL-6. Thus, the growth of FLAM-76 appeared to be regulated by the paracrine mechanism of IL-6. Alpha-interferon (alpha-IFN) inhibited the IL-6-dependent growth of FLAM-76 in doses greater than 1000 U/ml. FLAM-76 cells expressed CD38 (OKT10) and cell adhesion-associated antigens such as CD44 and CD54 (ICAM-1). Chromosome analysis revealed FLAM-76 to have a hypodiploid chromosome constitution with t(11;14)(q13;q32) abnormality, which frequently is seen in neoplasms of B-cell origin. Immunoglobulin (JH and Ck) gene rearrangement (but no BCL-1 gene rearrangement) was found in this cell line.
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PMID:The establishment of an interleukin-6-dependent myeloma cell line (FLAM-76) carrying t(11;14)(q13;q32) chromosome abnormality from an aggressive nonsecretory plasma cell leukemia. 151 3

The cytokine interleukin-6 (IL-6) is the major phosphoprotein secreted by human fibroblasts induced with interleukin-1 alpha (IL-1 alpha). We have determined that Ser54 is the predominant site of phosphorylation on the fibroblast-derived IL-6 polypeptide; the amino acid motif surrounding this site is reminiscent of the target site for the Golgi-associated protein (casein) kinase. It has been shown earlier that the IL-6 polypeptide follows the classical secretory pathway where N-linked glycosylation is detectable within the first 15 minutes of labeling with [35S]-methionine and O-linked glycosylation occurs between 15-30 minutes after the start of polypeptide synthesis. Pulse-chase experiments using [32P]-orthophosphate or [35S]-methionine as tracers indicated that phosphorylation of IL-6 occurred prior to its O-glycosylation suggesting that the de novo synthesized IL-6 polypeptide is rapidly, perhaps even cotranslationally, phosphorylated at an intravesicular site (in the endoplasmic reticulum and/or Golgi). When IL-1 alpha-induced fibroblasts were exposed to cycloheximide there was enhancement of the net de novo synthesis and secretion of IL-6 as followed by [35S]-methionine labeling ("superinduction") but the secreted cytokine was no longer phosphorylated as monitored by [32P] labeling. Thus, phosphorylation of the IL-6 polypeptide is not an obligatory requirement for secretion of this cytokine. Furthermore, IL-6 phosphorylation is inhibited by cycloheximide through a mechanism different from the drug's effects on polypeptide synthesis per se.
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PMID:Phosphorylation of interleukin-6 at serine54: an early event in the secretory pathway in human fibroblasts. 161 Mar 48

A new human multilineage myeloid leukemia cell line, MHH225, has been established in our laboratory from the bone marrow of a 60-year-old patient suffering from acute megakaryoblastic leukemia (M7); it provides a unique model for studying the effect of biologic and chemical agents on the lineage specificity of a multipotent myeloid leukemia clone containing a mixed population of megakaryoblast, erythroblast, and myeloblast cells in a serum-free culture. Morphologically, all 225 cells are large blast cells with basophilic cytoplasm containing no granules, large round nucleus containing 2-3 prominent nucleoli, and fine chromatin structure and a large nuclear/cytoplasm ratio. The MHH225 cells are CD34+HLA-DR+CD33+CD13+ with 57.6%, 28.3%, and 7.8% of them being CD41+, glycophorin A+, and CD15+, respectively, and all lymphoid-specific antigens are negative. The karyotype analysis of MHH225 cells revealed a deletion of the short arm of chromosome 7: del(7)(p13)-, a whole-arm translocation between the long arms of chromosomes 9 and 21: t(9;21)(q10;q10), and a chromosome 11 with an elongated long arm due to duplication of chromosome 11 material as well as to translocation of part of chromosome 9 onto 11q+. Also, chromosome 21 was deleted in some metaphases or showed a ring formation in other metaphases. Utrastructurally, MHH25 cells display a strong platelet peroxidase activity in the nuclear envelope and the endoplasmic reticulum. The MHH25 cells have been grown exponentially without growth factors or conditioned media or serum only in RPMI1640 culture medium. None of the myelopoietic growth factors, i.e., interleukin-3, GM-CSF, G-CSF, erythropoietin, or interleukin-6, has any effect on the proliferation and differentiation of MHH25 cells. The two, hematopoietic inhibitory cytokines, interferon-alpha and tumor necrosis factor-alpha, have only minimal growth inhibitory effect. Stem cell factor showed only weak growth-stimulatory effect on MHH225 cells but significantly inhibited chemotherapy-induced apoptosis in these cells. The new cell line MHH225 should constitute a useful model for studying stem cell antigen (CD34)-positive human multilineage myeloid leukemia cells carrying a deletion in the short arm of chromosome 7 and an aberration in chromosome 11 and provide a unique tool for investigating human hematopoietic stem cell biology and its cytokine regulation in serum-free cultures. To our knowledge, the MHH225 cell line is the first human CD34-positive leukemia cell line growing in serum-free cultures to be established.
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PMID:Establishment and characterization of a novel CD34-positive human myeloid leukemia cell line: MHH225 growing in serum-free culture. 754 28

Epidemiologic data indicate the crucial role of chronic hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) development. On the molecular level, HBV sequences are frequently integrated in hepatocellular DNA. However, in contrast to the woodchuck model, in which specific HBV-DNA integration is detectable in most cases, insertional (in-) activation of cellular genes seems to be a rare event in man. The recent discovery of transactivating functions exerted by HBx and truncated HBs(urface) proteins supports the notion that transactivation of cellular gene expression could be relevant to hepatocarcinogenesis. HBV transactivator sequences are present in 81% (21/26) of HCC tissues or hepatoma-derived cell lines. At least one transactivator protein was functional in all cases investigated so far. The 16.5-kDa HBx transactivator has been shown to stimulate gene expression from various cellular target sequences. In vitro, HBx displays oncogenic potential. A second type of transactivator is encoded in the preS/S region of HBV. In contrast to HBx, HBs transactivators require carboxyterminal truncation to gain their transactivating function. Unlike full-length M(iddle)HBs, the truncated MHBst is retained in the endoplasmic reticulum and not secreted into the surrounding medium. Cellular gene expression is stimulated by regulatory elements of the human proto-oncogenes c-fos and c-myc, as well as by the hepatic acute-phase interleukin-6 gene. Synthetic binding sites for the transcription factors NF-kappa B, AP-1, AP-2, SRE, and Sp1 render minimal promoters activatable. NF-kappa B-mediated transactivation by MHBst can be suppressed by radical scavenging antioxidants, indirectly suggesting that reactive oxygen intermediates are involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis. 760 73

Human aromatase cytochrome P450 catalyzes the ultimate reaction in the estrogen biosynthetic pathway by coupling with another enzyme, NADPH-cytochrome P450 reductase, in the endoplasmic reticulum. The expression of the gene encoding the enzyme (CYP19) is regulated, in part, by tissue-specific promoters through the use of alternative-splicing mechanisms. Recently, we have localized a transcriptional activating element at positions -2141 to -2115 relative to the major cap site of the gene, by transient expression analyses in human BeWo choriocarcinoma cells using the bacterial chloramphenicol acetytransferase reporter gene ligated with CYP19 promoter sequences which regulate expression in this tissue. Here, we report the isolation of a cDNA encoding a DNA-binding protein which binds specifically to the regulatory element. The deduced amino-acid sequence of the insert is identical to that corresponding to the DNA-binding domain and the dimerization domain of a transcription factor, nuclear factor interleukin-6 (NF-IL6), a member of the CCAAT/enhancer-binding protein (C/EBP) family. Studies using specific antibodies against members of the C/EBP family demonstrate that NF-IL6 is the major nuclear factor binding to the regulatory element in BeWo cells; nevertheless. C/EBP alpha also seems to be involved. Disruption of the NF-IL6-binding site within the regulatory element resulted in the disappearance of the transcriptional enhancing activity of the element, indicating that NF-IL6 is at least one of the nuclear factor(s) which enhances transcription through binding to the cis-acting element. These results indicate the intrinsic importance of NF-IL6 in the transcriptional regulation of CYP19 expression.
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PMID:Identification of a transcriptional regulatory factor for human aromatase cytochrome P450 gene expression as nuclear factor interleukin-6 (NF-IL6), a member of the CCAAT/enhancer-binding protein family. 763 40

Intrinsic glomerular cells, especially mesangial cells, are considered to be actively involved in the pathogenesis of glomerulonephritis (GN), but the precise mechanism(s) remains elusive. We have previously demonstrated that nephritogenic IgA immune complex can stimulate human mesangial cells (HMCs) to increase their production of interleukin-1 (IL-1) and interleukin-6 (IL-6). In order to evaluate the roles of cytokines such as IL-1 and/or IL-6 and mesangial cells as mediators of renal injury in GN, we have now examined the changes of HMCs and their secreted products in vitro, after stimulation with various concentrations of IL-1 and IL-6. Cytokine-activated HMCs showed the following changes: (1) increased cell size, with intracytoplasmic vacuoles, dilated endoplasmic reticulum, increased free ribosomes and polysomes, and mitochondrial swelling; (2) increased cell proliferation, reflected in thymidine incorporation and an increased proportion of S and G2/M phase cells by cell cycle analysis; (3) enhancement of IL-6 mRNA expression in HMCs with stimulation of IL-6 alone or IL-1 plus IL-6; and (4) release of large amounts of platelet activating factor (PAF), thromboxane B2 (TxB2), and superoxide anion. Taken together, these results strongly suggest that mesangial cell proliferation and increased production of immune/chemical mediators and superoxide anion can be directly induced by IL-1 plus IL-6. These changes may lead to ongoing renal injury.
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PMID:In vitro effects of interleukins on human mesangial cells: implications for glomerulonephritis. 774

Tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) antigenic sites were shown within the resident glomerular mesangial cells of lupus nephritis patients applying the colloidal gold immunocytochemical approach at the electron microscopic level. Using specific polyclonal antibodies against human recombinant (hr) TNF alpha and hrIL-6 in conjunction with the protein A-gold complex, TNF alpha and IL-6 were shown in the mesangial cells, being particularly associated with the membranes of the rough endoplasmic reticulum. In addition, IL-6 also was present in glomerular immune deposits and occasionally in glomerular epithelial cells. In normal renal tissue the TNF alpha and IL-6 immunoreactivities were undetectable. The specific presence of TNF alpha and IL-6 in pathological specimens was shown by several control experiments. Thus, our results offered morphological support that TNF alpha and IL-6 might play a role in human lupus nephritis. The data showed their synthesis by the mesangial cells and their possible participation in the progression to chronicity of the renal injury on secretion.
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PMID:Presence of tumor necrosis factor alpha and interleukin-6 in renal mesangial cells of lupus nephritis patients. 775 Sep 40

To determine the functional significance of endoplasmic reticulum chaperones in hematopoietic cells, we analyzed the expression and post-translational modification of BiP/GRP78 and GRP94 as well as the cytoplasmic chaperones HSP70 and HSC70 during the differentiation of a mouse myeloid leukemia cell line, M1. The amounts of BiP/GRP78 and GRP94 increased several-fold when M1 cells were induced to differentiate into macrophage-like cells by treatment with interleukin-6 (IL-6). Synthesis began to increase at 4 hr after IL-6 treatment. The phosphorylated form of BiP/GRP78 increased during the later stages of differentiation. These data suggested that the chaperone activity of BiP/GRP78 and GRP94 may be needed for differentiated macrophage-like cells or for the differentiation event itself, and that functionally different BiP/GRP78 accumulate during the differentiation of M1 cells.
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PMID:Expression and phosphorylation of BiP/GRP78, a molecular chaperone in the endoplasmic reticulum, during the differentiation of a mouse myeloblastic cell line. 779 66

Interleukin-6 (IL-6) exerts its action via a receptor complex composed of a ligand-binding subunit (gp80) and a signal transducer (gp130) which both belong to the hematopoietic receptor super-family. Very little is known about the biosynthesis and the biological half-lives of proteins of this superfamily. Therefore, we studied the biosynthesis and maturation of the interleukin-6 receptor and its signaling subunit gp130 by pulse chase experiments in stably transfected Madin-Darby canine kidney cells. We found that both proteins are synthesized as precursors with apparent molecular masses of 67 kDa and 130 kDa, respectively. These receptor forms are processed within 45-60 min into mature proteins of 82 kDa and 150 kDa containing complex-type oligosaccharides. The signal transducer gp130 shows a similar maturation in human hepatoma cells HepG2. The IL-6 receptor appears at the cell surface 45 min after completion of its synthesis in the endoplasmic reticulum. In both cell types studied, gp80 and gp130 are rapidly turned over with half-lives of 2-3 h. These half-lives were unaffected by the presence of the ligand IL-6.
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PMID:Biosynthesis and half-life of the interleukin-6 receptor and its signal transducer gp130. 803 1

Three forms of interleukin-6 (IL-6) have been constructed and stably transfected into human hepatoma cells (HepG2). Wild type IL-6 containing a signal peptide was rapidly secreted as a biologically active protein. IL-6 lacking the signal peptide accumulated within the cytoplasm of transfected cells. Surprisingly, IL-6 carrying a COOH-terminal extension of the amino acids Lys-Asp-Glu-Leu (KDEL) was not completely retained in the endoplasmic reticulum (ER). Complete retention in the ER was achieved when the 14 COOH-terminal amino acids of protein disulfide isomerase which include the KDEL signal were added to the COOH terminus of IL-6. This finding clearly demonstrates that the addition of the protein sorting signal KDEL alone is not sufficient for full retention of IL-6 in the ER. IL-6 accumulated in the cytoplasm and IL-6 retained in the ER failed to induce liver-specific acute-phase protein synthesis in the host cells, indicating that there is no intracellular role for IL-6 in signal transduction. Retention of IL-6 in the ER led to the prevention of surface expression of the IL-6 receptor protein gp80, making these cells unresponsive to IL-6. This phenomenon can be exploited in the future to generate transgenic animals which will become completely cytokine unresponsive in the tissues in which they express an ER retained cytokine.
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PMID:Intracellular retention of interleukin-6 abrogates signaling. 840 66


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