UNIPROT:P05231 - FACTA Search

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

Cellular turnover of the hematopoietic system is supported by a small population of cells termed hematopoietic stem cells. Stem cells are capable of self-renewal and differentiation into individual lymphomyeloid lineages. Available evidence indicates that the decision of a stem cell to self-renew or differentiate and the decision of a multipotential progenitor to select a lineage pathway during differentiation (commitment) are intrinsic to the progenitors and are stochastic in nature. In contrast, proliferative kinetics of the progenitors, namely, survival and expansion of the progenitors, appear to be controlled by a number of interacting cytokines. Whereas proliferation and maturation of committed progenitors are controlled by late-acting factors such as erythropoietin, macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-5, progenitors at earlier stages of development are controlled by a group of several overlapping cytokines. Interleukin-3, granulocyte/macrophage colony-stimulating factor, and interleukin-4 regulate proliferation of multipotential progenitors only after they are triggered to exit from dormancy state. Triggering of cycling of dormant primitive progenitors and proliferation of lymphohemopoietic primitive progenitors appear to require interactions of early acting cytokines including interleukin-6, granulocyte colony-stimulating factor, interleukin-11, interleukin-12, leukemia inhibitory factor, and steel factor.
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PMID:Hematopoiesis. 808 74

The enzyme gamma-glutamyl transferase (GGT) is a multifunctional enzyme that participates in a number of metabolic processes, including the conversion of leukotriene C4(LTC4) to leukotriene D4(LTD4). LTD4 is necessary for normal myeloid proliferation and differentiation. We have examined the ability of hematopoietic growth factors (HGF) to induce GGT enzyme activity and mRNA content in a HGF-responsive cell line (KG-1). Incubation of KG-1 with recombinant human cytokines interleukin-1 beta (IL-1 beta), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF), but not interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF) or monocyte colony-stimulating factor (M-CSF), results in significant increases in GGT enzyme activity. The increases in GGT activity are both dose- and time-dependent. In response to IL-1, increases in enzyme activity are seen by 6 hours and activity is maximal by 24 hours. GGT mRNA increases also occur and peak by 3 to 6 hours. These results indicate that induction of increases in GGT mRNA levels and enzyme activity occur in myeloid cells in response to HGFs. This induction, together with the requirement for LTD4 for normal granulopoiesis, supports a role for GGT in the cellular events occurring in myeloid cells in response to HGFs.
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PMID:Hematopoietic growth factor induction of gamma-glutamyl transferase in the KG-1 myeloid cell line. 809 53

Cytokines are key modulators of host immune and inflammatory responses. The expression of cytokine genes by tumor cells as a result of gene transfer has emerged as a novel strategy to augment in vivo host reactivity to various cancers. This review summarizes the knowledge obtained from experimental systems using this strategy and provides information on the current clinical trials employing this approach. In murine model systems, immunization with tumors expressing certain cytokines [e.g., tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-7 (IL-7), and granulocyte-macrophage colony stimulating (GM-CSF)] has demonstrated their ability to promote the generation of tumor-specific cytotoxic T lymphocytes by various mechanisms; in some cases, significant regressions of established microscopic tumor deposits result. Non T cell mechanisms of tumor killing, such as granulocytic inflammatory responses, may also be elicited by the localized elaboration of certain cytokines [e.g., IL-4, granulocyte colony-stimulating factor (G-CSF)]. The potency of antitumor immune potentiation by cytokines, however, remains to be established by further animal studies and emerging clinical trials. The genetic modification of tumors for the expression of immunostimulatory gene products holds promise as a new approach for active immunotherapy of cancer and for the isolation of effector cell populations for use in adoptive immunotherapy protocols.
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PMID:Experimental and clinical studies of cytokine gene-modified tumor cells. 818 97

Endothelial cells (EC) may regulate both local and systemic aspects of inflammation through the synthesis of cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), and interleukin-6 (IL-6). EC are known to synthesize these cytokines in response to interleukin-1 (IL-1 alpha), tumor necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS). In this paper, we illustrate the effect of interleukin-4 (IL-4) in reducing the synthesis of GM-CSF by EC stimulated with IL-1 alpha, TNF-alpha, or LPS. This is compared with the previously reported strong synergy between IL-4 and IL-1 alpha, TNF-alpha, or LPS in the synthesis of IL-6 by EC. No clear effect of IL-4 was seen in the synthesis of G-CSF or M-CSF. The range of concentrations of IL-4 at which these effects were seen was identical for both reduced GM-CSF synthesis and increased IL-6 synthesis. The effect of IL-4 on IL-6 synthesis was seen by 4 h of treatment, while that on GM-CSF was apparent between 4 and 8 h. It is suggested that these contrasting effects of IL-4 may reflect a biological role for this cytokine in the regulation of leukocytosis and the acute phase response.
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PMID:Contrasting effects of interleukin-4 on colony-stimulating factor and interleukin-6 synthesis by vascular endothelial cells. 832 81

Although mixed forms of Castleman's disease (CD) may occur, two classically recognized forms are the angiofollicular (hyaline vascular [V]) variant and the plasma cell (P) variant. The two forms of CD differ greatly in their clinical and histopathologic manifestations. Plasma cell CD is characterized by the presence of hyperplastic germinal centers (GCs) and sheets of plasma cells in the interfollicular areas. In this study we demonstrated an abundant expression of interleukin-6 (IL-6) in most GC B cells and in the numerous immunoblastoid B cells in the mantle zone and interfollicular areas in CD-P. Patients with CD-P also have an elevated serum IL-6 level. The increased IL-6 production is responsible for the marked plasma cell infiltration in lymph nodes and bone marrow as well as for the elevated gammaglobulin level in serum. In contrast, CD-V is distinguished by the presence of atrophic GCs, which often are populated by cytologically atypical follicular dendritic reticulum (FDR) cells, as well as by sheets of T-zone plasmacytoid histiocytes and increased numbers of capillaries in the interfollicular areas. In contrast to the findings in CD-P, we did not observe significant expression of IL-6 in GC cells or in immunoblastoid cells in CD-V; this may account for the paucity of plasma cells in this form of CD. The reason for the atypical changes in FDR cells as well as the increases in T-zone plasmacytoid histiocytes and capillaries seen in CD-V are not known inasmuch as no cytokines, such as IL-1, IL-4, IL-6, IL-7, IL-8, IL-9, tumor necrosis factor-alpha, granulocyte-macrophage colony-stimulating factor, or granulocyte colony-stimulating factor, were detectable in tissues. It is possible that in CD-V the atypical change in FDR cells could lead to a disturbance of B-lymphocyte/FDR cell interaction and subsequently to poor development of GCs. The study clearly indicates that the histopathologic and clinical features of CD vary greatly depending on the capacity of activated B cells to produce IL-6. However, lack of IL-6 secretion by GC cells alone cannot explain the histopathologic alterations in CD-V.
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PMID:Expression of interleukin-6 in Castleman's disease. 837 54

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

Human umbilical cord blood (CB) appears to be an exciting new source of transplantable stem cells for a variety of clinical conditions. In this study, we have attempted to further characterize the primitive progenitors in CB. First we analyzed the effects of early-acting growth factors on blast cell colony formation from CD34+ progenitors. Addition of Steel factor (SF), interleukin-6 (IL-6), or granulocyte colony-stimulating factor (G-CSF) to cultures containing interleukin-3 enhanced blast cell colony formation. These results indicated that cell cycle-dormant progenitors are present in CB. Next, based on results obtained in the murine system, we tested whether c-kit expression could separate the CB progenitors into cycle-dormant vs. cycle-active progenitors. Cells were separated into CD34+ c-kit-, c-kitlow, and c-kithigh. The results suggested that the c-kitlow population contains the majority of cycle-dormant progenitors and the c-kithigh population contains most of the forming cells were in the c-kitlow population, while the opposite is true for other colony-forming cells. Expression of c-kit may be useful in identifying CB progenitors with long-term engraftment capability.
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PMID:Characterization of c-kit expression by primitive hematopoietic progenitors in umbilical cord blood. 854 40

Human cytomegalovirus (CMV) infection is often associated with myelosuppression and acute inflammatory reaction in immunocompromised patients. We have previously documented that CMV exposure of bone marrow (BM) stromal cells reduces the capacity of these cells to support hematopoiesis because of a decreased production of colony-stimulating factors. This study examines the potential role of CMV on constitutive and lipopolysaccharide (LPS)-stimulated production of cytokines involved in inflammatory reaction, interleukin-6 (IL-6) and leukemia inhibitory factor (LIF) by BM stromal cells. The release of IL-6 was already detectable 2 hours post CMV-infection (2.5-fold increase in production) and the cumulative production of IL-6 after 5 days of infection was 23 +/- 1.2 ng/mL (ninefold increase in production). CMV was also able to induce a time-dependent production of LIF that was maximal 8 hours after CMV infection (2.5-fold increase in production). Concomitantly, there was no detectable release of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) by CMV-infected stromal cells. The similar IL-6 and LIF production in the presence of polymyxin B ruled out the possibility that this increase could be caused by contamination of the viral stock by endotoxin. In addition, ultraviolet-inactivated virus behaved similarly to live virus and caused the release of IL-6 and LIF. However, heat-inactivated CMV was unable to induce IL-6 and LIF secretion by BM stromal cells. The production of IL-6 and LIF was also evaluated after stimulation by LPS. After 5 days of CMV exposure, the LPS-stimulated production of IL-6 and LIF was significantly lower than uninfected controls. This LPS-induced release of cytokine production was found to be dependent of viral replication. The experiments have shown that CMV is a potent inducer of IL-6 and LIF with differential effect on constitutive and LPS-stimulated cytokine production by stromal cells; we suggest that CMV induction of IL-6 and LIF during the first hours of infection could play a role in CMV-induced inflammatory reaction. Moreover, our results show that human CMV can disturb the balanced cytokine network involved in the regulation of hematopoiesis.
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PMID:Human cytomegalovirus increases constitutive production of interleukin-6 and leukemia inhibitory factor by bone marrow stromal cells. 854 77

We have reported that serum granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) levels rise in patients with chemotherapy-induced myelosuppression. The aim of the present study was to determine whether other cytokines that function at different hematopoietic stages also fluctuate during chemotherapy-induced myelosuppression and whether the extent of cytokine level fluctuations correlate with myelosuppression severity. Fifteen patients participated in the study. Serum levels of stem cell factor (SCF), interleukin (IL)-1 alpha, IL-6, IL-3, granulocyte-macrophage CSF (GM-CSF) and G-CSF were analyzed before chemotherapy and during the myelosuppressive stage and correlations between cytokine levels and myelosuppression severity were examined. The results showed that both serum G-CSF and IL-6 levels rose in patients with chemotherapy-induced myelosuppression. The prechemotherapy serum G-CSF and IL-6 levels correlated well with their respective elevated levels during the myelosuppressive stage. The myelosuppression severity also correlated well with the extent of serum G-CSF level elevation. The serum IL-6 and G-CSF levels during the myelosuppressive stage correlated significantly. Serum SCF levels did not fluctuate significantly during myelosuppression, and IL-1, IL-3 and GM-CSF were rarely detected in serum even after chemotherapy. In the present study, the roles of IL-1 alpha, SCF, IL-3 and GM-CSF chemotherapy-induced myelosuppression were not clear.
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PMID:Serum cytokine level fluctuations in chemotherapy-induced myelosuppression. 855 62

To understand the structure-function relationship in the human interleukin-6 (IL-6) system, comparative studies were performed on the basis of NMR data obtained using the wild-type IL-6 and six mutants. In each of the six mutants, either Leu152, Leu159, Leu166, Leu168, Leu175, or Leu182, which exist in the C-terminal receptor-binding region, was substituted with Val. The resonance assignments of Val, Ile, Leu, and Phe residues were made by using specific double-labeling and site-specific mutagenesis strategies. On the basis of chemical shift and NOE data collected for six IL-6 mutants and those for the wild-type IL-6, we analyzed the structural changes induced by the substitution of each of the six Leu residues. The NMR data showed that substitution of Leu182 with Val (L182V) induced no structural change in IL-6, suggesting that Leu182 is located on the surface of the IL-6 molecule. A significant decrease in receptor-binding activity was observed in the L182V mutant. It was concluded that the side chain of Leu182 is directly involved in receptor binding. Substitution of Leu175 with Val (L175V) was shown to induce a significant structural change in IL-6. The NMR data are discussed on the basis of the location of four helix elements and an up-up-down-down helix topology of the predicted structure of IL-6 [Bazan, J.F. (1991) Neuron 7, 197-208]. It is possible that helix D bent more sharply toward helix B in the L175V mutant than in the wild-type IL-6 to maintain a closely packed and solvent-inaccessible core formed in the mutated region. It is suggested that the kink of helix D is related to the decrease in receptor-binding activity in the L175V mutant. On the basis of the observed NOE network, the folding topology of IL-6 was analyzed. A comparison of the folding topology of IL-6 with that of human granulocyte colony-stimulating factor determined by X-ray crystallography [Hill, C. P., Osslund, T. D., & Eisenberg, D. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 5167-5171] indicated that IL-6 has a significant similarity of folding topology to that of human granulocyte colony-stimulating factor.
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PMID:Folding topologies of human interleukin-6 and its mutants as studied by NMR spectroscopy. 855 85

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