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)

The "stromal" or adherent cells of long-term murine Dexter explant bone marrow cultures provide the best in vitro model of the bone marrow microenvironment. Colony-stimulating factor-1 (CSF-1) is produced constitutively by these cells and is easily detected, but most investigators have not found constitutive production of the other hemolymphopoietic cytokines. We have previously reported the detection of granulocyte-macrophage-CSF (GM-CSF) in murine stromal cultures and its induction by the lectin Pokeweed mitogen. The present studies analyzing stromal cytokine messenger RNA (mRNA) production by standard Northern blot analysis show constitutive production of mRNAs for CSF-1, GM-CSF, granulocyte-CSF (G-CSF), c-kit ligand (KL), and interleukin-6 (IL-6), but not IL-3, IL-4, or IL-5 by 3-week irradiated or nonirradiated murine Dexter stromal cells. Exposure of stromal cells to Pokeweed mitogen or IL-1 16 hours before RNA harvest induces the messages for GM-CSF, G-CSF, KL, and IL-6, but not IL-3, IL-4, IL-5, or CSF-1. Polymerase chain reaction amplification of cDNA made with reverse transcriptase from stromal RNA using two separate sets of IL-3-specific primers shows the presence of IL-3 message in irradiated stromal cells, which is only detectable with this more sensitive technique. The factor-dependent cell lines FDC-P1 and 32D are supported by the stromal cells without the addition of exogenous growth factors, demonstrating a cytokine activity in these cultures that is inhibited by the addition of anti-IL-3 or anti-GM-CSF antibodies. These data indicate that murine Dexter stromal cells constitutively produce CSF-1, GM-CSF, G-CSF, IL-6, KL, and IL-3. This growth factor production could explain the support of granulocyte, macrophage, and megakaryocyte production and stem cell maintenance in Dexter-type long-term murine bone marrow cultures.
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PMID:Biologic significance of constitutive and subliminal growth factor production by bone marrow stroma. 137 43

Congenital neutropenia (Kostmann's syndrome [KS]) is an autosomal recessive syndrome that is characterized by profound neutropenia, resulting in major clinical infections and death. Since the neutropenia and symptoms in KS improve in response to exogenous administration of granulocyte colony-stimulating factor (G-CSF), we studied bone marrow cytokine (G-CSF, granulocyte-macrophage CSF [GM-CSF], and interleukin-6) production under both basal and stimulated conditions. No differences in G-CSF, GM-CSF, or IL-6 gene expression were found in bone marrow stromal cells between normal controls and KS patients, and all three cytokines were detected by enzyme-linked immunosorbent assay (ELISA) in medium conditioned by bone marrow stromal cells from normal donors and patients with KS. Each KS patient tested had detectable, functional G-CSF in their own serum before exogenous G-CSF administration. Since G-CSF production appeared normal in KS patients, we then asked whether we could detect structural defects in the signaling portion of G-CSF receptor genes. Polymerase chain reaction (PCR) amplification of the G-CSF receptor transmembrane region alone, and of the transmembrane plus cytosolic portions of the receptor, yielded the size products predicted from the sequences of the normal G-CSF receptor. Single-strand conformational polymorphism (SSCP) analysis of G-CSF receptor PCR products demonstrated no variance in structural conformation between KS patients and normal subjects. These results demonstrate that bone marrow stromal cells in patients with KS secrete normal concentrations of functional G-CSF and suggest that the neutropenia in KS patients is caused by an inability of neutrophilic progenitor and precursor cells to respond to normal, physiologic levels of G-CSF. Such a defect, clinically responsive to pharmacologic doses of G-CSF, might be caused by defects in the post-G-CSF receptor signal transduction pathway.
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PMID:Granulocyte colony-stimulating factor (G-CSF) production and G-CSF receptor structure in patients with congenital neutropenia. 751 Jan 42

We established a human bone marrow stromal cell line (Saka) by infecting marrow adherent cells from semisolid marrow cultures with a recombinant simian virus-40 (SV40) virus. The cells expressed SV40 large tumor antigen, had a fibroblast-like shape, and expressed fibronectin and vimentin. They did not contain detectable alkaline phosphatase activity; express myeloid, lymphoid, or factor VIII-associated antigens; or develop adipocyte-like characteristics with dexamethasone treatment. Polymerase chain reaction analysis of Saka cell RNA detected expression of messenger RNAs for interleukin-6 (IL-6), IL-1 beta, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, stem cell factor, and the 1,25-dihydroxyvitamin D3 receptor. Coculture of Saka cells with human marrow mononuclear cells enhanced formation of osteoclast-like multinucleated cells (MNC) in long term human bone marrow cultures. These MNC expressed calcitonin receptors and formed resorption lacunae on dentine. In contrast, coculture of marrow mononuclear cells with other SV40-transformed human marrow stromal cell lines did not increase MNC formation. Conditioned medium from Saka cells or coculture of bone marrow and Saka cells separated by a Millipore membrane did not enhance MNC formation. Addition of a neutralizing antibody to IL-6 or IL-1 beta blocked the effects of Saka cells on MNC formation. These results suggest that marrow stromal cells enhance osteoclast formation in part through direct cell to cell contact and production of IL-6 and/or IL-1 beta.
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PMID:Development and characterization of a human marrow stromal cell line that enhances osteoclast-like cell formation. 753 99

Although stem cell factor (SCF) has been identified as a critical cytokine for the development of human mast cells from their progenitors, the effects of other cytokines on human mast cells are less well understood. We examined the effects of several cytokines on the survival of human mast cells of 100% purity generated in suspension cultures of umbilical cord blood mononuclear cells in the presence of 100 ng/mL recombinant human (rh) SCF and interleukin-6 (IL-6). Mast cells suspended in conventional serum-containing medium died over a period of 2 to 6 days after the withdrawal of SCF and IL-6. The cells became pyknotic and underwent DNA fragmentation characteristic of apoptosis. The addition of SCF, IL-3, IL-4, IL-5, or IL-6 to the cultures in both serum-containing and serum-free medium prolonged their survival in a dose-dependent manner. Some other cytokines, such as IL-2, IL-9, IL-10, IL-11, tumor necrosis factor-alpha, transforming growth factor-beta 1, and nerve growth factor, had no survival-promoting effect at 100 ng/mL. Preincubation of mast cells with SCF, IL-4, IL-5, or IL-6 for 24 hours during sensitization with IgE enhanced IgE/anti-IgE antibody-induced histamine release from mast cells, whereas IL-3 showed a negligible effect. Polymerase chain reaction amplification of alpha-chains of IL-3 receptor (R), IL-4 R, IL-5 R, and IL-6 R yielded products of the correct size predicted from the sequence of each receptor. The binding assay using 125I-labeled IL-3 indicated that these mast cells bear receptors for IL-3. These findings suggest that IL-3, Il-4, IL-5, and IL-6, which are mainly produced by T-helper 2 lymphocytes, might regulate the functions of human mast cells in vivo via specific receptors in allergic reactions.
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PMID:Effects of T-helper 2-type cytokines, interleukin-3 (IL-3), IL-4, IL-5, and IL-6 on the survival of cultured human mast cells. 757 37

We have analysed a panel of different Burkitt's lymphoma (BL) and lymphoblastoid cell lines (LCLs) for the expression of IL6 and IL6 receptor (IL6R). Epstein-Barr-Virus (EBV) positive or negative BL cell lines and the corresponding lymphoblastoid cell lines (LCL), derived from EBV immortalized mononuclear cells of the BL patients, were tested for the expression of IL6 mRNA and protein by Northern blot experiments and ELISA, and for the expression of the IL6R mRNA and protein by Northern blot Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR) and flow cytometry. Our results demonstrate that six out of 19 Burkitt's lymphoma cell lines produced IL6 constitutively. All three cell lines infected with the EBV substrain B95-8 (B95-8 convertants) produced IL6, in contrast to the original EBV negative lines and to the cell lines infected with the EBV substrain P3HR1 (P3HR1 convertants). The produced IL6 was biologically active as shown by proliferation of the IL6 dependent cell line TEPC 1033 C2. The two BL cell lines with the highest level of IL6 production (190 pg/ml and 550 pg/ml) expressed in addition IL6R molecules on the cell surface. Monoclonal antibodies directed against IL6 did not inhibit the growth of these two BL cell lines, thus excluding autocrine stimulation in these lines. IL6R expression could be further demonstrated in all LCLs analysed, in five out of seven EBV positive BLs and two out of three B95-8 convertants, but only in one out of the six EBV negative BL cell lines. Our results suggest that EBV in immortalized B cells and in Burkitt's lymphoma cells can promote IL6 receptor expression.
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PMID:IL6 and IL6 receptor expression in Burkitt's lymphoma and lymphoblastoid cell lines: promotion of IL6 receptor expression by EBV. 762 42

Haemopoiesis is often depressed in patients suffering from acquired immune deficiency syndrome (AIDS). Although several mechanisms have been postulated to be responsible for depressed haemopoiesis in AIDS patients, the aetiology of this disorder is still unknown. We hypothesized that failure of the stromal microenvironment may account for part of the haemopoietic defect observed in patients with AIDS. We therefore studied a murine model of AIDS (MAIDS) caused by infection with LP-BM5 virus to determine the ability of bone marrow cells from immunodeficient mice to establish long-term stromal cultures. In addition, normal and MAIDS mice received AZT (2 mg/ml) in their drinking water for up to 1 month to determine the effects of AZT treatment in vivo on the ability of bone marrow cells to support haemopoiesis in long-term cultures. Decreased numbers of non-adherent cells were observed in long-term bone marrow cultures (LTBMC) of MAIDS mice when compared to cultures derived from normal mice. Decreased numbers of non-adherent cells were observed in cultures of bone marrow cells from AZT-treated normal mice, when compared to untreated normal controls. Cells from AZT-treated MAIDS mice produced the smallest number of non-adherent cells. BFU-E and CFU-G/M were decreased in cultures of MAIDS mice when compared to those of normal mice. AZT-treatment further decreased the number of colony-forming cells in both MAIDS mice and normal cultures. Stromal cell function of MAIDS mice was also assessed by inoculating non-adherent cells from normal mice onto confluent irradiated MAIDS LTBMC. Stroma from MAIDS mice was unable to support haemopoietic function of normal bone marrow cells. Polymerase chain reaction (PCR) analysis of steady state levels of cytokine mRNAs of cells from confluent cultures revealed that levels of interleukin-6 mRNA were unchanged in MAIDS mice, as compared to normal controls, but the levels of GM-CSF were decreased in MAIDS mice. These data suggest that LP-BM5 MuLV infection alters the functioning of the haemopoietic stroma and that one mechanism of this depression in haemopoiesis may be via alterations of cytokine production.
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PMID:Impaired ability of bone marrow cells from immunodeficient mice to establish long-term cultures. 791 27

We wished to establish the presence of interleukin-1 (IL-1) in human sweat (5) and clarify its origin and mechanism of secretion. IL-1 alpha concentration ([IL-1 alpha]) in clean sweat from the back increased with the sweat rate, plateauing at the maximal sweat rate ([IL-1 alpha]max). The mean [IL-1 alpha]max was 545 pg/ml (n = 17) for men and 1,324 pg/ml for women in back sweat. The mean [IL-1 alpha]max for axillary sweat in men was 1,568 (n = 6). Palmar sweat was 9.2 ng/ml (n = 5) for IL-1 alpha and 7.9 ng/ml for IL-1 beta. [IL-1 alpha]max decreased to one-third that of the first sweat test, when second sauna sweat tests were conducted after 2 h of continuous sweating on the same day. Western blot analysis of the purified sweat IL-1 alpha fraction revealed bands at 17, 29, and 33 kDa. Immunoreactive IL-1 alpha was localized mainly in the secretory coil lumen, intercellular canaliculi, cytoplasm, mitochondria, and near plasma membranes. Polymerase chain reaction revealed the presence of IL-1 alpha mRNA in the sweat gland and in cultured human eccrine secretory coil cells. Both sweat IL-1 alpha and human recombinant IL-1 alpha at 500 pg/ml strongly stimulated interleukin-6 and interleukin-8 production in cultured fibroblasts. We conclude that the IL-1 alpha-like immunoreactive substance in sweat is IL-1 alpha itself, is derived from the sweat gland, and is biologically active at concentrations normally present in fresh sweat.
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PMID:Interleukin-1 alpha in human sweat is functionally active and derived from the eccrine sweat gland. 816 Aug 91

With the advent of recent molecular studies, nonspherocytic hemolytic anemia caused by red blood cell pyruvate kinase (PK) deficiency is now considered to be caused by a structural mutation of the PK-LR gene. Because PK deficiency is a monogenic disorder, the introduction of the normal PK gene into a patient's bone marrow stem cells should cure the disorder. To study the feasibility of gene therapy for PK deficiency, we first constructed the PK retrovirus pMNSM-hPK using human liver-type PK (LPK) cDNA and obtained a producer cell line of E86/AmPK. By using the supernatant of this virus-producer cell, we transduced NIH/3T3 cells, mouse leukemic cells (NFS60, FDCP-2), and human leukemic cells (K562, HEL). The expression of human LPK enzyme activity was ascertained from the retrovirally transduced NIH/3T3 cells. Northern blot analysis demonstrated the expression of the human LPK mRNA in each transduced cell line. Furthermore, bone marrow stem cells (c-kit+, Lin-, Thy-1lo) sorted by fluorescence-activated cell sorting were also transduced by the producer cells in the presence of interleukin-3 and interleukin-6, and were transplanted into lethally irradiated C57BL/6 mice. Polymerase chain reaction analysis demonstrated the expression of human LPK mRNA in both the peripheral blood and hematopoietic organs on day 30 and on day 135 of bone marrow transplantation.
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PMID:Retrovirus-mediated gene transfer of human pyruvate kinase (PK) cDNA into murine hematopoietic cells: implications for gene therapy of human PK deficiency. 816 97

Embryonic hematopoiesis is initiated in part in the blood islands of the yolk sac. Previous confocal microscopic analysis has shown that the CD34 antigen, a mucin-like cell surface glycoprotein that is expressed by hematopoietic progenitors and all endothelial cells of the adult and embryo, is also found on a subset of luminal hematopoietic-like cells in the yolk sac blood islands as well as on the vascular endothelium lining these early hematopoietic locations. We show here that, as in all other hematopoietic sites thus far examined, immunoaffinity-purified CD34+ nonadherent cells from murine yolk sacs contain the vast majority of erythroid and myeloid progenitor cell colony forming activity. To examine the developmental interactions between these CD34+ hematopoietic progenitor cells of the yolk sac and the CD34+ yolk sac endothelium, we have immunaffinity-purified adherent endothelial cells from day 10.5 yolk sacs using CD34 antiserum and produced cell lines by transformation with a retrovirus expressing the polyoma middle T antigen. Analysis of these cell lines for CD34, von Willebrand's factor, FLK 1 and FLT 1 expression, and capillary growth in Matrigel indicates that they appear to be endothelial cells, consistent with their original phenotype in vivo. Coculture of yolk sac CD34+ hematopoietic cells on these endothelial cell lines results in up to a 60-fold increase in total hematopoietic cell number after approximately 8 days. Analysis of these expanded hematopoietic cells showed that the majority were of the monocyte/macrophage lineage. In addition, examination of the cultures showed the rapid formation of numerous cobblestone areas, a previously described morphologic entity thought to be representative of early pluripotential stem cells. Scrutiny of the ability of these endothelial cell lines to expand committed progenitor cells showed up to a sixfold increase in erythroid and myeloid colony-forming cells after 3 to 6 days in culture, consistent with the notion that these embryonic endothelial cells mediate the expansion of these precursor cells. Polymerase chain reaction analyses showed that most of the cell lines produce FLK-2/FLT-3 ligand, stem cell factor, macrophage colony-stimulating factor, leukemia-inhibitory factor, and interleukin-6 (IL-6), whereas there is a generally low or not measurable production of granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, IL-1, IL-3, transforming growth factor beta-1, erythropoietin, or thrombopoietin. The output of mature hematopoietic cells from these cocultures can be modified to include an erythroid population by the addition of exogenous erythropoietin. These data suggest that endothelial cell lines derived form the yolk sac provide an appropriate hematopoietic environment for the expansion and differentiation of yolk sac progenitor cells into at least the myeloid and erythroid lineages.
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PMID:CD34+ endothelial cell lines derived from murine yolk sac induce the proliferation and differentiation of yolk sac CD34+ hematopoietic progenitors. 854 34

Inflammation following an infection induces a range of nonspecific symptoms of sickness in animals and humans. The cytokine interleukin-1 (IL-1) mediates many of the brain-mediated symptoms of sickness. Binding sites for IL-1 have been found in mouse brain, but not in the brains of rats. This raises questions as to the involvement of these neuronally localized IL-1 binding sites in the induction of sickness symptoms. Based on observations of IL-1 receptor mRNA in close vicinity to the vasculature in the mouse and rat brain, we studied the possibility that endothelial cells in the rat brain exhibit IL-1 receptors to transduce information to the brain. Ligand binding studies reveal that cultured endothelial cells of adult rat brain exhibit specific binding sites for rat IL-1beta. Polymerase chain reaction experiments demonstrated that mRNA of the type I but not that of the type II IL-1 receptor is present in rat brain endothelial cells. Incubation of these endothelial cells with recombinant rat IL-1beta showed a dose-dependent increase in interleukin-6, prostaglandin E(2), and prostacyclin secretion. Intravenous administration of rat IL-1beta to adult rats enhanced prostaglandin E(2) immunoreactivity in endothelial cells of the brain microvasculature. These results indicate that functional type I IL-1 receptors are present on endothelial cells of adult rat brain. We postulate that circulating IL-1 can be translated by brain endothelial cells into other signals such as interleukin-6 or prostaglandins that have access to the brain and induce sickness symptoms.
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PMID:Interleukin-1 receptors on rat brain endothelial cells: a role in neuroimmune interaction? 864 70


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