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)

Mast cells represent a potential source of interleukin-6 (IL-6) and other cytokines that have been implicated in host defense, tissue maintenance/remodeling, immunoregulation, and many other biologic responses. In acquired immune responses to parasites or allergens, the extensive IgE-dependent activation of mast cells via Fc epsilonRI can result in the release of large quantities of biogenic amines that are stored in the cells' cytoplasmic granules as well as the production of lipid mediators and many cytokines; these products together can orchestrate an intense inflammatory response. We now report that activation of mouse mast cells via c-kit, the receptor for the pleiotropic survival/growth factor, stem cell factor (SCF), can induce the release of IL-6. Upon challenge with SCF, bone marrow-derived cultured mouse mast cells (BMCMCs) released amounts of IL-6 that were greater than 100-fold more than those produced by unstimulated cells, but that were substantially less than those produced in response to IgE and specific antigen. Moreover, BMCMCs released IL-6 upon challenge with concentrations of SCF that resulted in little or no detectable release of tumor necrosis factor-alpha, leukotriene C4, histamine, or serotonin. These findings indicate that SCF, a widely expressed protein that is critical for mast cell development and survival, can also regulate the differential release of mast cell mediators.
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PMID:Differential release of mast cell interleukin-6 via c-kit. 910 82

Transfer of "anti-HIV-1 genes" into hematopoietic stem cells of human immunodeficiency virus-1 (HIV-1)-infected individuals may be a potent therapeutic approach to render mature cells arising from transduced stem cells resistant to the destructive events associated with HIV-1 infection. To determine the feasibility of gene therapy for acquired immunodeficiency syndrome in individuals already infected with HIV-1, granulocyte colony-stimulating factor mobilized peripheral blood CD34+ cells were isolated from HIV-1-infected individuals and transduced with retroviral vectors containing three different anti-HIV-1-genes: the Rev binding domain of the Rev Responsive Element (RRE decoy) (L-RRE-neo), a double hammerhead ribozyme vector targeted to cleave the tat and rev transcripts (L-TR/TAT-neo), and the trans-dominant mutant of rev (M10) (L-M10-SN). As a control, a vector mediating only neomycin resistance (LN) was used. After 3 days of transduction on allogeneic stroma in the presence of stem cell factor, interleukin-6 (IL-6), and IL-3, the cultures were G418-selected, and then challenged with HIV-1(JR-FL) and a primary HIV-1 isolate. Compared with the control cultures, the L-RRE-neo-, L-TR/TAT-neo-, and L-M10-SN-transduced cultures displayed up to 1,000-fold inhibition of HIV-1 replication after challenge with HIV-1(JR-FL) and the primary HIV-1 isolate. Growth of the hematopoietic cells in long-term bone marrow culture was not perturbed by the presence of any of the anti-HIV-1 genes. This study shows that anti-HIV-1 genes can be introduced into CD34+ cells from individuals already infected with HIV-1, and strongly inhibit HIV-1 replication in primary monocytes derived from the CD34+ progenitors.
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PMID:Inhibition of human immunodeficiency virus-1 (HIV-1) replication after transduction of granulocyte colony-stimulating factor-mobilized CD34+ cells from HIV-1-infected donors using retroviral vectors containing anti-HIV-1 genes. 911 67

The response of megakaryocytes and cytokines to the administration of romurtide, a synthetic muramyl dipeptide derivative, was investigated in monkeys with myelosuppression by carboplatin-treatment. Romurtide increased the number of megakaryocytes and promoted the shift of megakaryocytes towards high ploidy class indicative of the promotion of the proliferation and maturation of megakaryocytes. The serum levels of interleukin-6, stem cell factor, and erythropoietin elevated significantly before the enhanced response of megakaryocytes induced by romurtide was observed. Romurtide also enhanced production of colony-stimulating factors (CSFs), such as granulocyte-CSF, macrophage-CSF, and granulocyte-macrophage CSF by monkey mononuclear cells. The stimulating effect of romurtide on the production of those cytokines and CSFs is likely to be responsible for the subsequent promotion of the proliferation and maturation of marrow megakaryocytes.
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PMID:Romurtide, a synthetic muramyl dipeptide derivative, promotes megakaryocytopoiesis through stimulation of cytokine production in nonhuman primates with myelosuppression. 914 Dec 12

Bone marrow (BM) failure associated with cytomegalovirus (CMV) infection is a feared complication after clinical BM transplantation. Experiments in long-term BM cultures have indicated that BM stromal cells (BMSC) are targets of productive CMV infection, but an in situ infection of BM stroma remained to be documented, and the pathomechanism is open to question. Here we describe a murine in vivo model of lethal CMV aplastic anemia (CMV-AA). The reconstitution of hematopoietic progenitor cells expressing stem cell factor (SCF) receptor was found to be defective in CMV-AA. While murine CMV replication in permissive parenchymal tissues is cytolytic, the hematopoietic cord was found to be a site of very limited virus production with foci of reticular BMSC expressing the intranuclear viral IE1 protein, but with only a few BMSC positive for viral genome in the in situ hybridization. XX-XY BM chimeras were established in order to quantitate Y-chromosome-tagged BMSC by a PCR specific for the male-sex-determining gene Tdy. This approach revealed that murine CMV infection is not associated with a significant loss of BMSC. Despite the physical integrity of the stromal network, the functional integrity of the stroma was impaired. While housekeeping genes were expressed normally in BMSC of infected mice, the expression of genes encoding the essential hemopoietins SCF, granulocyte colony-stimulating factor, and interleukin-6 was markedly reduced. In conclusion, the mechanism of BM failure is not a stromal lesion but an insufficient stromal function. These findings explain CMV-AA as a manifestation of multiple hemopoietin deficiency.
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PMID:Bone marrow failure by cytomegalovirus is associated with an in vivo deficiency in the expression of essential stromal hemopoietin genes. 915 53

Interleukin-1 and interleukin-6 are two of a great number of cytokines involved in the synergistic regulation of hematopoietic progenitor cell growth. Clinical descriptions that suggest several therapeutic uses for interleukin-1 and interleukin-6 have appeared. In either high-dose chemotherapy or bone marrow transplantation, either cytokine can be myeloprotective or myelorestorative and can increase platelet recovery. Also, both cytokines could be useful in stimulating the peripheralization of stem-progenitor cells in vivo. In vitro, both cytokines have proven useful in the ex vivo expansion of hematopoietic progenitor cells and subsequent reinfusion in patients undergoing autologous bone marrow transplantation. Mechanistically, both stimulate production of other regulators of hematopoiesis, induce increased cell surface expression of receptors for hematopoietic growth factors, and shorten the cell cycle transit time of progenitors. Differences in the actions of interleukin-6 and interleukin-1 on highly enriched and purified stem cells are starting to emerge, with proliferation in stem cell factor and interleukin-6 preserving marrow-repopulating ability of stem cells, and the proliferative stimulus of stem cell factor and interleukin-1 leading to more rapid differentiation.
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PMID:Hematologic effects of interleukin-1 and interleukin-6. 937 Dec 84

Immunoassays have recently made it possible to specifically measure the circulating levels of hematopoietic growth factors. This is helping us to understand the in vivo regulation of hematopoiesis under conditions of steady state or stress, providing insights into the physiological roles of hematopoietic growth factors and their importance in the pathogenesis of disease. As mediators of pathological processes, hematopoietic growth factors may be targets for antagonist therapy in some diseases. Exogenous hematopoietic growth factors may also be useful therapeutically to augment physiological responses, so understanding hematopoietic growth factor regulation and serum levels may assist the development of specific therapies. Hematopoietic growth factor levels may also serve as tumor markers and assist prognostication or monitoring during the clinical course of an illness. The growth factors of particular interest include the four classic colony-stimulating factors: granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, and multi-colony-stimulating factor, also known as interleukin-3. Other cytokines with hematopoietic growth factor activity include interleukin-1, interleukin-6, interleukin-11, stem cell factor (also known as Steel factor or mast cell growth factor), and leukemia inhibitory factor.
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PMID:Measurement and clinical significance of circulating hematopoietic growth factor levels. 937 Dec 87

To protect bone marrow cells from the toxicity of chemotherapy, a multidrug resistant gene or a dihydrofolate reductase gene has been introduced into stem cells. These genes, however, are not capable of conferring refractoriness to alkylating agents (AA), which are some of the most commonly used agents in chemotherapy regimens. In the present study, an attempt was made to endow human stem cell (CD34+ cells) with resistance to cyclophosphamide, a well-known AA, and adriamycin (ADM) by transducing the glutathione-S-transferase pi (GST-pi) gene whose product is thought to detoxify AA by conjugating them with glutathione and to remove a toxic peroxide formed by ADM. The gene transduction was carried out retrovirally with a virus titer of 1 x 10(5) FFU/ml, employing a recombinant fibronectin fragment; transduction efficiency was extremely low without the fragment. Incubation with interleukin-6 and stem cell factor enhanced the expression of fibronectin ligands VLA4 and VLA5 on CD34+ cells. This enhanced expression of VLA4 and VLA5 was considered to facilitate a close contact of the CD34+ cell to the retroviral vector via fibronectin fragments and the subsequent transduction process. The GST-pi gene-transduced CD34+ cells formed almost 3- and 2.5-fold more CFU-GM than neo gene-transduced CD34+ cells in the presence of 2.5 microg/ml of 4-hydroperoxycyclophosphamide (4-HC), an active form of cyclophosphamide, and 30 ng/ml ADM, respectively. The transfectants formed an appreciable number of colonies, even at higher concentrations of these drugs (5.0 microg/ml of 4-HC, 50 ng/ml of ADM) whereas neo gene-transduced or nontransduced CD34+ cells formed no colonies at all, indicating the possibility of selecting out the transfectants by exposing them to these anticancer drugs. Thus, we were able to demonstrate that transduction of the GST-pi gene confers resistance to cyclophosphamide as well as to ADM, and therefore this approach can be applied clinically for high-dose chemotherapy.
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PMID:Fibronectin fragment-facilitated retroviral transfer of the glutathione-S-transferase pi gene into CD34+ cells to protect them against alkylating agents. 938 56

Human cultured mast cells (HCMCs) grown from cord blood mononuclear cells in the presence of stem cell factor (SCF) and interleukin-6 (IL-6) expressed tryptase but no or low chymase in their cytoplasm. The addition of IL-4 to these cells strikingly increased chymase expression. Consequently, the activity of chymase was significantly higher in IL-4-treated mast cells than that in IL-4-nontreated mast cells, whereas the activity of tryptase and histamine content were comparable in both cells. Electron microscopic immunocytochemistry also showed that secretary granules containing chymase increased in IL-4-treated mast cells. Interestingly, the IL-4-induced increase of chymase expression in HCMCs was accompanied by morphological maturation of the cells. Cytoplasmic projections were few in IL-4-nontreated HCMCs, and a small number of secretary granules were observed, most of which were empty or partially filled with discrete scrolls with rough particles showing immaturity. In contrast, IL-4-treated HCMCs had extremely abundant cytoplasmic projections and had many secretary granules filled with electron-dense crystal materials. Taken together, immature HCMCs grown only with SCF and IL-6 expressed tryptase with no or a low amount of chymase, and addition of IL-4 promoted cell maturation together with the expression of both tryptase and a high amount of chymase. Our findings will raise a possibility of a linear pathway of human mast cell development from tryptase single positive mast cells into tryptase and chymase double positive mast cells as the cells mature and will suggest that this maturation process is promoted by IL-4.
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PMID:Interleukin-4 promotes the development of tryptase and chymase double-positive human mast cells accompanied by cell maturation. 941 84

We investigated the effect of alpha-phenyl N-tert-butylnitrone (PBN), a spin trap reagent, on the proliferation of murine hematopoietic progenitor cells in vitro. During the addition of PBN to the liquid cultures of murine bone marrow cells containing a combination of interleukin-3, interleukin-6 and the c-kit ligand/stem cell factor, colony-forming cells in vitro (CFC) and the colony-forming unit in the spleen (CFU-S) increased about 1.6-fold and 2.0-fold, respectively, higher than the control culture. These effects were not observed when using dimethyl sulfoxide, which has the ability to scavenge radicals, and 5,5-dimethyl-1-pyrroline N-oxide, another spin trap reagent. Analysis of cultured cells from a 7-day liquid culture with PBN revealed that the ratio of the intracellular glutathione (GSH) and GSH/GSSG (oxidized GSH) content was higher than the control. Adding thiol N-acetylcysteine, a thiol reagent and a precursor of intracellular GSH, also showed similar effects on the liquid culture of murine hematopoietic progenitor cells and the level of intracellular GSH. In contrast, adding DL-buthionine-[S,R]-sulfoximine, a gamma-glutamylcysteine synthetase inhibitor, decreased the intracellular GSH level and did not increase the number of CFC and CFU-S. These results suggest that PBN regulates the content of intracellular thiol molecules, and the possibility of a relationship between the intracellular redox state and the proliferation and differentiation of hematopoietic stem cells.
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PMID:Effects of alpha-phenyl N-tert-butylnitrone, a spin trap reagent, on the proliferation of murine hematopoietic progenitor cells in vitro. 943 16

Passaged bone marrow fibroblasts (PBMF) fail to maintain long-term hemopoiesis in culture unlike stromal adhesive layers of long-term culture of the bone marrow (LTCBM). What differs PBMF from LTCBM stromal cells in terms of the above ability we attempted to find out using immunocytochemical microscopy and flow cytometry. There were no differences as to protein production of the extracellular matrix, production of granulocytic-macrophagal colony-stimulating factor, stem cell factor, transforming growth factor beta, interleukin-1 beta and interleukin-6. The difference lies in inability of PBMF to produce granulocytic colony-stimulating factor (GCSF). It is evident that production of GCSF by stromal cells of the bone marrow is essential for maintenance of myelopoiesis in LTCBM.
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PMID:[The production of granulocyte colony-stimulating factor by stromal bone marrow populations]. 948 53


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