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

Using colony assays in semi-solid media, several investigators have shown that supernatants (SN) of normal and malignant human B-cells can stimulate the growth of granulocyte-macrophage (GM) progenitor cells. So far macrophage colony-stimulating factor (M-CSF) and interleukin-6 (IL-6) have been identified as potential colony-stimulating activity (CSA) present in B-cell SN. However, other CSAs such as GM-CSF, G-CSF, IL-1-beta, IL-3, and IL-4 may also be candidates in this respect. Several human B-cell lines (CL) were screened for the expression of the respective genes at the mRNA and protein level. Constitutive production of GM-CSF was detected in the lymphoblastoid CL Wi-L2-729-HF2 and in the Burkitt line Raji. The signal intensity of specific transcripts and the amount of protein being secreted increased upon exposure to the phorbol ester PMA. The hybridoma line HB-564 also expressed the GM-CSF gene, but required prior stimulation with PMA. 3H-thymidine incorporation of Raji and Wi-L2-729-HF2 cells was unchanged in the presence or absence of a specific neutralizing sheep anti-GM-CSF serum, suggesting that GM-CSF did not serve as an extracellular autocrine growth factor. The expression of the GM-CSF gene was independent of the proliferative state (log phase growth versus plateau phase growth) and of the presence of serum in cultures of the respective CL. The expression of G-CSF, IL-1-beta, IL-3, and IL-4 genes was not detectable in the CL at the mRNA level.
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PMID:Screening for expression of cytokines with hematopoietic growth factor activity by permanent human B-cell lines. 188 24

We examined whether recombinant cytokines enhance the in vitro platelet production of interleukin-3 (IL-3)-induced human megakaryocytic colonies (Meg-colony). We classified Meg-colonies into four categories based on platelet production during in situ observation on day 14: type 0, absence of cytoplasmic processes in a colony; type 1, one to three processes in at least one megakaryocyte in a colony; type 2, four to eight processes; type 3, more than nine processes or division of cytoplasm. Type 3 colonies were considered to be platelet-producing. In control cultures, type 1 Meg-colonies were dominant, followed by type 2, type 3 and type 0. Of the cytokines added at the initiation of culture, interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), and granulocyte/macrophage colony stimulating factor (GM-CSF) significantly increased the number of colonies. Furthermore, these three cytokines significantly elevated the proportion of type 3 colonies. Interleukin-4 (IL-4), granulocyte-CSF, macrophage-CSF and erythropoietin did not affect the colony count or distribution of colony type. IL-1 alpha, IL-6 and GM-CSF also significantly elevated the proportion of type 3 colonies, even when added to the culture on days 8 or 11. These results indicate that IL-1 alpha, IL-6 and GM-CSF promote platelet production of in vitro Meg-colonies.
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PMID:Megakaryocyte potentiating activity of IL-1, IL-6 and GM-CSF as evaluated by their action on in vitro human megakaryocytic colonies. 191 39

Current evidence suggests that the development of allosensitized cytotoxic T lymphocytes within sponge matrix allografts takes place primarily in situ and may be regulated by the secretory products of the cells infiltrating the graft. In vitro studies have implicated IL-2, IL-4, and IL-6 in CTL development. We have reported that TNF-alpha, macrophage colony-stimulating factor, IL-1, IFN-alpha, and IFN-beta are present in the allograft, but that IL-2 and IL-4 cannot be detected at any time using specific bioassays. In this study, we found significantly higher levels of IL-6 within the allografts compared with the syngeneic grafts. Peak IL-6 activity coincided with the appearance of allosensitized CTL in the allografts. IL-6 concentration in the serum of sponge allografted mice was less than 1% of that found in the graft. The sponge fluid exhibited both hybridoma growth factor and hepatocyte-stimulating factor activities in vitro, and both these activities were neutralized by antibody to murine IL-6 but not by antibody to murine IL-1-beta or TNF-alpha. Messenger RNA for murine IL-6 was detected in the graft-infiltrating cells. The high level of IL-6 found in the allograft coincident with the appearance of cellular immunity suggests that this cytokine might play some role in the development of allospecific CTL in vivo.
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PMID:Evidence that production of interleukin 6 within the rejecting allograft coincides with cytotoxic T lymphocyte development. 200 23

The capacity of human cultured mesangial cells to produce soluble factors potentially relevant for mechanisms of inflammation and immunity at the glomerular site was analyzed. The nature of the secreted factors initially was investigated by Northern blot analysis using total cellular RNAs isolated from resting and activated mesangial cells. On exposure of mesangial cells to human recombinant interleukin-1 beta (IL-1 beta), high levels of interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) mRNAs were detected. Similar transcripts were found after stimulation with human recombinant tumor necrosis factor-alpha (TNF-alpha). Active secretion of IL-8 was documented by radioimmunoassay in supernatants of mesangial cells activated by either IL-1 beta or TNF-alpha. Using an in vitro migration assay, supernatants from resting mesangial cells were found to be devoid of any chemotactic activity for granulocytes or monocytes. On stimulation with IL-1 beta, however, mesangial cell supernatants expressed MCP-1 biologic activity detected as induction of a strong migratory response for human monocytes but not for granulocytes. In addition, IL-1 beta and TNF-alpha induced high levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) mRNAs. Similarly IL-1 beta and TNF-alpha induced the interleukin-6 (IL-6) gene and active secretion of its mature protein. These data strongly support an effector role for mesangial cells in modulating immune-inflammatory responses in glomeruli. Release of cytokines may activate not only infiltrating inflammatory cells through short paracrine pathways, but also mesangial cells themselves through an autocrine pathway.
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PMID:Interleukin-1 beta and tumor necrosis factor-alpha induce gene expression and production of leukocyte chemotactic factors, colony-stimulating factors, and interleukin-6 in human mesangial cells. 201 80

An elucidation of the interaction between the bone marrow microenvironment and hematopoietic stem cells is critical to the understanding of the molecular basis of stem cell self renewal and differentiation. This interaction is dependent, at least in part, on direct cell to cell contact or cellular adhesion to extracellular matrix proteins. Long-term bone marrow cultures (LTMC) provide an appropriate microenvironment for maintenance of primitive hematopoietic stem cells and a means of analyzing this stem cell-stromal cell interaction in vitro. Although LTMC have been successfully generated from murine and human bone marrow, only limited success has been reported in a primate system. In addition, few permanent stromal cell lines are available from nonmurine bone marrow. Because the primate has become a useful model for large animal bone marrow transplant studies and, more specifically, retroviral-mediated gene transfer analysis, we have generated immortalized bone marrow stromal cell lines from primate bone marrow using gene transfer of the Simian virus large T (SV40 LT) antigen. At least one stromal cell line has demonstrated the capacity to maintain early hematopoietic cells in long-term cultures for up to 4 weeks as measured by in vitro progenitor assays. Studies were undertaken to characterize the products of extracellular matrix biosynthesis and growth factor synthesis of this cell line, designated PU-34. In contrast to most murine bone marrow-derived stromal cell lines capable of supporting hematopoiesis in vitro that have been examined, the extracellular matrix produced by this primate cell line includes collagen types I, laminin. Growth factor production analyzed through RNA blot analysis, bone marrow cell culture data, and factor-dependent cell line proliferation assays includes interleukin-6 (IL-6), IL-7, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, M-CSF, leukemia inhibitory factor, and a novel cytokine designated IL-11. This immortalized primate bone marrow stromal cell line may be useful in maintaining early progenitor cells for experimental manipulation without the loss of reconstituting capacity and as a potential source of novel hematopoietic growth factors.
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PMID:Stromal cell-associated hematopoiesis: immortalization and characterization of a primate bone marrow-derived stromal cell line. 201 98

We report a phase I study in cancer patients being treated with i.v. bolus injections of highly purified lipopolysaccharide (LPS) Salmonella abortus equi. Twenty-four patients with disseminated cancer received escalating doses of LPS at 2-week intervals. Dose escalation was performed in six dose levels treating 3-6 patients at each level. Dose levels 1 and 2 consisted of 0.15 and 0.3 ng/kg, respectively. Further dose escalation up to 5.0 ng/kg was enabled by pretreatment with ibuprofen, which attenuated the constitutional side effects of LPS. The maximum tolerated dose was 4.0 ng/kg with dose-limiting toxicity being World Health Organization grade III hepatic toxicity. Hematological changes included transient decreases in WBCs affecting granulocytes, monocytes, and lymphocytes in a marked different pattern. Endogenous cytokine release occurred in an LPS dose-dependent manner as measured by tumor necrosis factor-alpha, interleukin-6, and macrophage colony-stimulating factor serum levels. Moderate antitumor activity in colorectal cancer was observed in the case of 2 patients. Phase II trials of LPS are currently in progress.
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PMID:Phase I trial of intravenously administered endotoxin (Salmonella abortus equi) in cancer patients. 202 32

We investigated the capacity of mouse bone marrow-derived macrophages (BMDM) to produce interleukin 1 (IL 1), interleukin-6 (IL 6), and tumor necrosis factor (TNF) upon lipopolysaccharide (LPS) stimulation. BMDM were allowed to differentiate either in the presence of conditioned medium (from WEHI-3 or L cells), or in the presence of recombinant cytokines (IL 3, macrophage-colony stimulating factor [M-CSF], or granulocyte/macrophage-colony stimulating factor [GM-CSF]). Cells were maintained in culture up to 3 weeks and tested at different times. Significant spontaneous cytokine production was never observed. BMDM rapidly acquired the capacity to elaborate cytokine upon LPS activation. LPS-triggered BMDM were able to produce IL 1, IL 6, and TNF, throughout the culture period, although 2- to 3-week-old cells lost their ability to release IL 1 while accumulation of intracellular IL 1 remained unchanged. The dissociation between synthesis and release of IL 1 was not correlated with a significant modification of the specific binding of LPS onto the cell surface.
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PMID:Lipopolysaccharide-induced production of cytokines by bone marrow-derived macrophages: dissociation between intracellular interleukin 1 production and interleukin 1 release. 210 27

This study examines the effect of leukemia inhibitory factor (LIF) on preosteoblastic rat calvaria (RCT-1) cells, which acquire osteoblastic properties when treated with retinoic acid (RA). LIF potentiated the increase in alkaline phosphatase (AP) activity produced by RA. The LIF effect was time and dose dependent (EC50, approximately 1 pM). The earliest effects on AP activity were detected at 48 h, and maximal effects were observed after 72 h. RA increased AP mRNA about 2-fold at 3 h and 6-fold at 6 and 12 h. LIF further increased AP mRNA to 18-fold at 12 h. After RA treatment AP mRNA returned to control levels at 24 h, but in the presence of LIF, AP mRNA remained elevated at 24 and 72 h of treatment. When given alone, LIF had no effect on either AP activity or mRNA levels. Tumor necrosis factor-alpha and 1,25-dihydroxyvitamin D3 also potentiated the RA induction of AP, and interleukin-6 had a small effect, whereas granulocyte macrophage colony-stimulating factor had no effect. LIF alone had a small inhibitory effect on type 1 collagen mRNA, but did not oppose the stimulatory effect of RA. Consistent with these biological actions, LIF receptors were demonstrated on these cells. [125I]LIF bound to RCT-1 cells at 0 C with an apparent dissociation constant of 20 pM, and it was found that these cells express an average of 300 receptors/cell. Scatchard analyses showed a single class of high affinity binding site. LIF was internalized with an endocytic rate constant for occupied receptors of 0.03 min-1, and the apparent equilibrium dissociation constant at 37 C was 358 pM. These findings suggest that osteoblast precursor cells are among the target cells of LIF.
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PMID:Leukemia inhibitory factor binds with high affinity to preosteoblastic RCT-1 cells and potentiates the retinoic acid induction of alkaline phosphatase. 211 91

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) exert multiple effects on the proliferation, differentiation, and function of myeloid lineage cells through their interaction with specific cell-surface receptors. There is a considerable degree of overlap in the biological effects of these two growth factors, but little is known about the mechanisms of postreceptor signal transduction. We have investigated the effects of GM-CSF and IL-3 on protein tyrosine-kinase activity in a human cell line, MO7E, which proliferates in response to either factor. Tyrosine-kinase activity was detected using immunoblotting with a monoclonal antibody (MoAb) specific for phosphotyrosine. GM-CSF and IL-3 were found to induce a nearly identical pattern of protein tyrosine phosphorylation using both one- and two-dimensional gel electrophoresis. Tyrosine phosphorylation of two cytosolic proteins in particular was increased more than 10-fold, a 93-Kd protein (pp93) and a 70-Kd protein (pp70). Tyrosine phosphorylation of pp93 and pp70 was observed within 1 minute, reached a maximum at 5 to 15 minutes, and gradually decreased thereafter. Other proteins of 150, 125, 63, 55, 42, and 36 Kd were also phosphorylated on tyrosine in response to both GM-CSF and IL-3, although to a lesser degree. Tyrosine phosphorylation was dependent on the concentration of GM-CSF over the range of 0.1 to 10 ng/mL and on IL-3 over the range of 1 to 30 ng/mL. Stimulation of MO7E cells with 12-0-tetradecanoyl-phorbol-13-acetate (TPA) or cytokines such as G-CSF, M-CSF, interleukin-1 (IL-1), interleukin-4 (IL-4), interleukin-6 (IL-6), interferon gamma, tumor necrosis factor (TNF), or transforming growth factor-beta (TGF-beta) did not induce tyrosine phosphorylation of pp93 or pp70, suggesting that these two phosphoproteins are specific for GM-CSF-or IL-3-induced activation. The extent and duration of phosphorylation of all the substrates were increased by pretreatment of cells with vanadate, an inhibitor of protein-tyrosine phosphatases. Importantly, culture of MO7E cells with vanadate (up to 10 mumol/L) resulted in a dose-dependent increase in GM-CSF-or IL-3-induced proliferation of up to 1.8-fold. These results suggest that tyrosine phosphorylation may be important for GM-CSF and IL-3 receptor-mediated signal transduction and that cell proliferation may be, at least partially, regulated by a balance between CSF-induced protein-tyrosine kinase activity and protein-tyrosine phosphatase activity.
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PMID:Signal transduction of the human granulocyte-macrophage colony-stimulating factor and interleukin-3 receptors involves tyrosine phosphorylation of a common set of cytoplasmic proteins. 216 6

The AF1-19T rat cell line has been found to produce an activity that acts synergistically with colony-stimulating factor 1 (CSF-1) to stimulate primitive high proliferative potential colony-forming cells (HPP-CFC) in mouse bone marrow (BM) that appear to be the same as those stimulated by the combination of 5637-cell-conditioned medium (CM) plus CSF-1 or recombinant human (rh) interleukin 1 (IL-1) plus recombinant murine (rm) interleukin 3 (IL-3) plus CSF-1. AF1-19T also produced granulocyte-macrophage colony-stimulating factor (GM-CSF), which could be separated from this synergistic activity by gel filtration followed by hydroxylapatite chromatography. Results obtained from the mouse thymocyte costimulation assay for IL-1, the hybridoma growth factor assay for interleukin 6 (IL-6), the ability to stimulate HPP-CFC, and the ability to block this stimulation with an antibody to murine IL-1 alpha suggest that the synergistic activity in AF1-19T-CM is probably a mixture of IL-1 activity and IL-6 or an IL-6-like activity. Other workers have described a progenitor cell population in mouse BM (CFU-A) that forms large colonies in response to AF1-19T-CM plus CSF-1 or GM-CSF plus CSF-1. Experiments involving the kinetics of recovery after 5-fluorouracil treatment and generation of progenitors suggest that the GM-CSF-plus-CSF-1-responsive progenitors, and hence CFU-A, are a more mature cell type than the more primitive HPP-CFC, responsive to 5637-cell-CM plus CSF-1 or rhIL-1 plus rmIL-3 plus CSF-1.
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PMID:Progenitor cells in murine bone marrow stimulated by growth factors produced by the AF1-19T rat cell line. 218 22


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