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

We have studied the in vivo effects of recombinant human interleukin-6 (rhIL-6) on hematopoiesis in eight healthy and nine irradiated cynomolgus monkeys. Of the healthy animals, three received rhIL-6 alone (10 micrograms/kg/d, subcutaneously [SC]), one received rhIL-6 in combination with rhIL-3 (10 micrograms/kg/d, SC), one received rhIL-6 in combination with recombinant cynomolgus granulocyte-macrophage colony-stimulating factor (rcGM-CSF; 10 micrograms/kg/d, SC), two received rhIL-6 in combination with recombinant human granulocyte-CSF (rhG-CSF; 10 micrograms/kg/d, SC), and one received rhIL-6 in combination with recombinant human leukemia inhibitory factor (rhLIF; 10 micrograms/kg/d, SC). All animals were treated for at least 2 weeks with rhIL-6 or the above mentioned combinations. rhIL-6 alone significantly increased the peripheral blood platelet counts (2- to 3.5-fold). The platelets reached a plateau between days 10 and 15 of treatment. No synergistic effects on platelet numbers were observed when rhIL-6 was combined with rhIL-3, rcGM-CSF, rhG-CSF, or rhLIF. In addition to rhIL-6, only rhLIF increased the platelet numbers when administered alone. To test whether rhIL-6 might also protect the animal from thrombocytopenia or shorten the time of thrombocytopenia after irradiation, we treated nine animals with total body irradiation (3.8 Gy). Six of the animals were additional treated with rhIL-6 (4 with 10 micrograms/kg/d; and 2 with 100 micrograms/kg/d) from day -1 or +1 to day 28 post irradiation. In these animals, rhIL-6 at the same dose effective in healthy animals (10 micrograms/kg/d) was not capable of protecting the animals from platelet nadir. However, when pegylated rhIL-6 was used at a dosage of 100 micrograms/kg/d post irradiation, the mean of the nadirs was 71,000/microL as compared with 39,000/microL in control animals and the time of thrombocytopenia was shorter (3 v 5 days). In all animals (healthy and irradiated), rhIL-6 did not increase the number of bone marrow megakaryocytes but induced a right shift of DNA ploidy in megakaryocytes. These data suggest that IL-6 acts as "thrombopoietin"-like activity, but not as "megakaryocyte-CSF"-like activity.
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PMID:In vivo effects of interleukin-6 on thrombopoiesis in healthy and irradiated primates. 768 32

Following reverse transcription and PCR amplification, the human interleukin-6 (IL-6) cDNA was cloned from total RNA of activated human tonsillar mononuclear cells. Southern blot showed the presence of specific band, and its DNA sequence demonstrated that the fragment was 650 bp in length, spanning the complete coding region and part of 5' and 3'-untranslated regions. The human IL-6 sequence seemed to be well conserved. One nucleotide change at 429 position was observed, but this change did not affect the amino acid composition. After inserting the cloned cDNA into retroviral vector XM-6, the recombinant was packaged in PA317 cells and the amphotropic virus titer reached 5 x 10(5) CFU/ml. Human IL-6 was expressed in mammalian cell line SP2/0 cells, after being infected by the constructed retrovirus. The G418 resistant SP2/0 cells secreted IL-6. Its supernatant was able to maintain in vitro growth of the IL-6 dependent T1165 cell line. Northern blot analysis of the transfected SP2/0 cells showed significantly elevated IL-6 message, being consistent with the result of T 1165 bioassay. The expression was stable during the 12 month period of observation. The hybridoma cells, formed after fusion of the transfected SP2/0 cells and lymphocytes, exhibited accelerated growth.
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PMID:[Stable and efficient expression of human interleukin-6 cDNA in mammalian cells after gene transfer]. 129 Dec 90

It has been proposed that certain cytokines secreted by islet-infiltrating leukocytes may be involved in the pathogenesis of insulin-dependent diabetes mellitus by participation in beta-cell destruction. In the present study, the impact of various cytokines on replication and long-term insulin secretion by pancreatic beta-cells was investigated. To this end, fetal rat pancreatic islets containing a high fraction of beta-cells were exposed in culture for 1-3 days to interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interferon-alpha (IFN-alpha), and interleukin-6 (IL-6) at different concentrations. It was found that IL-1 beta markedly decreased beta-cell DNA synthesis during the first day of exposure, an effect that vanished after 2 days and was turned into a potent and dose-dependent stimulation by 3 days of exposure. At this latter time point, IL-1 beta also amplified the mitogenicity of growth hormone (GH) and 16.7 mM glucose. In contrast, basal as well as glucose- and GH-stimulated insulin secretion was consistently suppressed by IL-1 beta from days 1-3. IL-1 beta also lowered the islet adenosine 3',5'-cyclic monophosphate (cAMP) content at all time points studied. However, addition of the stimulatory cAMP analogue Sp-diastereomer of adenosine 3',5'-cyclic monophosphothioate or pertussis toxin, which themselves enhanced DNA synthesis and insulin secretion, failed to prevent the inhibitory actions of IL-1 beta on these parameters, making it unlikely that a decrease in cAMP is an important event in transduction of the inhibitory effects of the cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Differential effects of cytokines on long-term mitogenic and secretory responses of fetal rat pancreatic beta-cells. 132 36

Transcription of interleukin-6 (IL-6) gene in human HepG2 and HeLa cells was induced by treatment with interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), phorbol 12-myristate 13-acetate, or dibutyryl cyclic AMP. These agents enhanced the expression of chloramphenicol acetyltransferase (CAT) activity in cells transfected with chimeric CAT genes driven by the transcriptional regulatory regions of human IL-6 gene. Both induced and basal levels of CAT expression were severely repressed upon co-transfection of expression vectors encoding the adenoviral E1A289R or E1A243R protein. The conserved region 1 of E1A proteins was required for this activity. IL-6-CAT expression could also be induced by co-transfecting expression vectors containing cDNAs of the catalytic subunit of protein kinase A or c-jun. E1A repressed transcriptional induction by these agents as well. Similar inhibition was observed when a CAT gene driven by the NF kappa B element of the IL-6 gene was used as a reporter plasmid. In a cell line stably transfected with the E1A gene, IL-1 or TNF-alpha failed to induce IL-6 mRNA. Electrophoretic mobility shift assays were carried out with nuclear extracts of these cells using, as probes, the NF kappa B element or the multiple regulatory element of the IL-6 gene. With either probe, additional faster migrating DNA-protein complexes were formed in the extracts of E1A-expressing cells as compared with the extracts of the corresponding control cells. Experiments with NF kappa B antibody revealed differences between the different DNA-protein complexes formed in the extract of E1A-expressing cells. These observations suggest that E1A represses IL-6 gene transcription by interfering with the formation of appropriate DNA-protein complexes.
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PMID:Transcriptional repression of interleukin-6 gene by adenoviral E1A proteins. 133 71

We report the isolation and characterization of the growth arrest and DNA-damage-inducible gene, GADD153, from human cells and show that it is localized in the region 12q13.1-q13.2 on chromosome 12. Comparison of the human gene with the previously described hamster gene revealed a high level of conservation in both the structural and regulatory regions of the genes. Each is composed of four exons with intron/exon junctions maintained at the identical positions. The human Gadd153 protein shares 91% identity with the hamster protein in amino acid sequence, and 78% identity in nucleotide sequence. A 900-bp fragment of 5' flanking sequence from the human gene, when linked to the bacterial cat reporter gene, was found to exhibit promoter activity in HeLa cells which could be further activated by treatment with the DNA alkylating agent, methyl methanesulfonate. Sequence analysis indicated that the human promoter region is relatively G+C-rich and contains putative binding sites for multiple transcription factors, including recognition sites for TATA- and CAAT-binding proteins, six Sp1-binding sites, an activator protein-1 binding site, an E-26-specific sequence-binding protein-1 DNA-binding site, and four interleukin-6 response elements. Many of these sites are also present in an identical position in the hamster gene suggesting they may play an important role in regulating GADD153 expression.
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PMID:Isolation, characterization and chromosomal localization of the human GADD153 gene. 133 68

Interleukin-6 (IL-6) stimulates growth and immunoglobulin (lg) secretion in Epstein-Barr virus (EBV)-infected B cells. In this study, we demonstrate that B-cell activation by IL-6 is associated with an initial induction of c-myc, a gene believed to act as a competence factor for increased RNA transcription and DNA replication, and by increases in DNA, RNA, and protein synthesis, as well as cell number. IL-6 increased the levels of lg mRNA per cell in comparison to a non-cycle-dependent cellular mRNA, tubulin. However, two other cell cycle-dependent cellular mRNAs, c-myc and actin, were also induced by IL-6 comparable to lg mRNAs. Increased levels of lg mRNA were not due to significant changes in RNA turnover, but appeared to reflect increased levels of RNA transcription. Together, these findings support the notion that IL-6 plays an important role as a stimulator of DNA and RNA synthesis in EBV-activated B cells.
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PMID:Regulation of B-cell growth and immunoglobulin gene transcription by interleukin-6. 137 Mar 87

The proto-oncoprotein c-Rel is a member of the nuclear factor kappa B transcription factor family, which includes the p50 and p65 subunits of nuclear factor kappa B. We show here that c-Rel binds to kappa B sites as homodimers as well as heterodimers with p50. These homodimers and heterodimers show distinct DNA-binding specificities and affinities for various kappa B motifs. In particular, the c-Rel homodimer has a high affinity for interleukin-6 (IL-6) and beta interferon kappa B sites. In spite of its association with p50 in vitro, however, we found a lymphoid cell-specific nuclear factor in vivo that contains c-Rel but not p50 epitopes; this factor, termed IL-6 kappa B binding factor II, appears to contain the c-Rel homodimer and preferentially recognizes several IL-6 kappa B-related kappa B motifs. Although it has been previously shown that the IL-6 kappa B motif functions as a potent IL-1/tumor necrosis factor-responsive element in nonlymphoid cells, its activity was found to be repressed in lymphoid cells such as a Jurkat T-cell line. We also present evidence that IL-6 kappa B binding factor II functions as a repressor specific for IL-6 kappa B-related kappa B motifs in lymphoid cells.
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PMID:A lymphoid cell-specific nuclear factor containing c-Rel-like proteins preferentially interacts with interleukin-6 kappa B-related motifs whose activities are repressed in lymphoid cells. 137 88

Investigations of mast cell biology have often used immortalized cultured cells which are continuously proliferating. In vivo, however, only 2% or fewer tissue mast cells are actively dividing. We used aphidicolin, an inhibitor of DNA polymerase to induce a proliferative arrest of murine mast cells characterized by an inhibition of cell division and thymidine incorporation, with accumulation of cells in G1 and early S phase of the cell cycle. Uridine incorporation and cell viability were not significantly impaired. DNA synthesis and cell division both resumed rapidly upon removal of the drug. Morphometric analysis demonstrated that cell size, granule size, and number of granules per cell were all increased in aphidicolin-treated cells. Proliferative arrest also produced a 14-fold increase in cellular histamine content, but did not alter the proteoglycans synthesized by the cell. The level of c-myc mRNA was reduced in aphidicolin-arrested cells, but returned to the level observed in untreated cells within 1 hr of removal of the drug. In contrast, the constitutive steady-state RNA levels of tumour necrosis factor-alpha (TNF-alpha), B2-microglobulin, actin, and the c-Ha-ras and c-fes protooncogenes were not altered. Aphidicolin-induced proliferative arrest did not prevent the induction of TNF-alpha, interleukin-6 (IL-6) and c-fos genes in response to calcium ionophore. Both the magnitude and induction kinetics of these messages were similar in aphidicolin-treated and untreated cells. We conclude that proliferative arrest results in morphological and biochemical changes suggestive of cellular maturation, but inhibition of cell division alone is not sufficient to alter mast cell phenotype. Although optimal c-myc expression appears to require active proliferation, cytokine gene induction can occur in non-dividing cells. These data suggest that the proliferative quiescence of in vivo mast cells should not preclude their involvement in biological events via elaboration of multi-functional cytokines.
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PMID:Aphidicolin-induced proliferative arrest of murine mast cells: morphological and biochemical changes are not accompanied by alterations in cytokine gene induction. 138 41

With the aim of using interleukin-6 (IL-6)-inducible promoters to express transgenes, we investigated the long-term consequences of high levels of IL-6 in mice. As a first step, we generated transgenic mice constitutively expressing the murine IL-6 at a level sufficient to induce IL-6-responsive genes. These mice were analyzed with respect to the indirect and direct consequences of elevated IL-6 expression over a time period of about 2 years. Although biologically active IL-6 was expressed from the transgene and different alterations could be documented (less immature B cells in bone marrow, expression of IL-6-inducible liver genes), the mice appeared healthy and could easily be used for breeding. Only in mice older than 18 months did we find a high incidence of lymphomas associated with different tissues. These results indicate that the side effects of long-term treatment with IL-6 are relatively moderate, and that IL-6 might be used to mediate the expression of heterologous genes in the context of functional studies.
DNA Cell Biol 1992 Oct
PMID:Long-term consequences of interleukin-6 overexpression in transgenic mice. 138 46

Human recombinant hepatocyte growth factor (HGF) added to primary cultures of rat hepatocytes stimulates synthesis of some acute phase proteins, especially alpha-2-macroglobulin. As indicated by changes in mRNA abundance HGF increases alpha-2-macroglobulin production at the pretranslational level. Interleukin-6, the main acute-phase cytokine, does not show synergy with HGF in enhancing synthesis of alpha-2-macroglobulin, and inhibits HGF-induced DNA-synthesis. On the other hand, dexamethasone potentiates the effects of HGF on synthesis of DNA and acute phase proteins by cultured rat hepatocytes.
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PMID:Modulation of acute phase protein synthesis in cultured rat hepatocytes by human recombinant hepatocyte growth factor. 138 85


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