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)

Serial observations of blast cell colony development from spleen cells of mice treated with 5-fluorouracil (5-FU) four days earlier revealed that either form of human interleukin-1 (IL-1 alpha or IL-1 beta) hastens the emergence of interleukin-3 (IL-3)-dependent blast cell colonies. This activity was essentially indistinguishable from the effect of interleukin-6 (IL-6) or granulocyte colony-stimulating factor (G-CSF) in the same system, an effect that we have ascribed previously to a shortening of the G0 period of the dormant stem cells. We also analyzed the time courses of colony formation from cultures of day-2 post-5-FU marrow cells supported by IL-1 alpha, IL-6, or G-CSF alone or in combination with IL-3. In the presence of IL-3, G-CSF and IL-6 but not IL-1 alpha hastened the development of colonies and increased the numbers of multilineage colonies relative to cultures of IL-3 alone. This observation, together with our previous data from the human system, suggests that the synergistic effect of IL-1 is likely due to induction of secondary growth factors, including IL-6 and G-CSF, by accessory cells in culture. The effect of IL-6 on G0 was confirmed by analysis of the cycling status of progenitor cells in short-term culture. While neither IL-3 nor IL-6 alone had any effect on the cycling status, the combination of factors resulted in a rapid recruitment of quiescent cells into cell cycle (within 48 hours) as represented by a twofold increase in the numbers of multipotential progenitors and a significant increase in the sensitivity of these cells to 3H-thymidine with high specific activity. Combinational testing of all of these synergistic factors revealed that the target cell populations for the IL-1, IL-6, and G-CSF overlap considerably, suggesting that they all may act through a common mechanism. This is further supported by our finding that cells from blast cell colonies grown in the presence of a combination of any one of the synergistic factors with IL-3 replate with higher efficiency and yield more multilineage secondary colonies than those from colonies grown in IL-3 alone. These findings provide further evidence that IL-1, IL-6, and G-CSF serve to integrate the immediate host responses to infection through augmentation of effector cells and antibody production as well as the longer term host responses by recruitment of dormant hemopoietic stem cells into active cell cycling.
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PMID:Synergistic factors for stem cell proliferation: further studies of the target stem cells and the mechanism of stimulation by interleukin-1, interleukin-6, and granulocyte colony-stimulating factor. 326 95

The chromosomal DNA segment of human B cell stimulatory factor-2 (BSF-2/IL-6) was isolated and characterized by nucleotide sequence analysis. The human BSF-2/IL-6 gene consists of five exons and four introns and its organization shows a distinctive similarity to granulocyte colony-stimulating factor gene. The two genes have the same number of exons and introns and the size of each exon is strikingly similar. The BSF-2/IL-6 mRNA was found to be constitutively expressed in a human T cell leukemia virus-1 transformed T cell line, TCL-Na1, a bladder cell carcinoma line, T24, and an amnion derived cell line, FL. The BSF-2/IL-6 mRNA was also found to be inducible with interleukin-1 beta in an astrocytoma line, U373 and a glioblastoma line, SK-MG-4. S1 mapping and primer extension analyses showed the presence of multiple initiation sites and the preferential utilization of a different initiation site for each individual tissue tested.
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PMID:Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. 350 Aug 52

The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) on cytokine profile was evaluated in a case of severe congenital neutropenia. The plasma levels of cytokines were measured before and during rhG-CSF therapy. These included G-CSF, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha, interleukin-1 beta, interleukin-2 (IL-2), interleukin-3 (IL-3), interleukin-4, interleukin-6 (IL-6), and tumor necrosis factor-alpha. Soluble interleukin-2 receptor (sIL-2R) was measured serially during rhG-CSF therapy. Lymphocyte subpopulations including CD2, CD3, CD4, CD8, CD19, CD20, and CD25 were also measured, rhG-CSF was administered once daily as a 30-min infusion. The patient was treated with increasing dose levels of 100, 200, 400, 800, and 1,600 micrograms/m2/day. The level of endogenous G-CSF was elevated to 334 pg/ml before treatment and GM-CSF, IL-2, IL-3, and IL-6 were slightly elevated. Clinically, he showed a moderate response to a high dose of rhG-CSF (1,600 micrograms/m2/day). Plasma levels of G-CSF markedly increased during therapy but plasma levels of other cytokines did not show significant changes during therapy and lymphocyte subpopulations did not significantly change. A drastic increase in sIL-2R expression was observed after rhG-CSF infusion and an increase in sIL-2R expression occurred even before a major increase in granulocyte counts. These results showed that a high dose rhG-CSF therapy may influence the cytokine network as judged by the increased sIL-2R expression.
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PMID:Cytokine profile during high-dose rhG-CSF therapy in severe congenital neutropenia. 750 1

Treatment of neoplastic diseases is followed by a variety of infectious complications. Neutropenia and functional defects of phagocytes are common consequences of cancer and its treatment and contribute to an increased susceptibility to infections. Cytokines with hematopoietic growth stimulatory and/or immunoenhancing properties, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin-3, interferon-gamma, macrophage colony-stimulating factor, interleukin-1, and interleukin-6 have been shown to either have clinical utility in patients with cancer and neutropenia or offer the promise to do so. GM-CSF and G-CSF, for example, have been shown to reduce the incidence of fever and infectious complications in patients with cancer and neutropenia. The role of cytokines for the treatment of defined infections (e.g., invasive mycoses) is under investigation.
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PMID:Perspectives on the use of cytokines in the management of infectious complications of cancer. 750 61

We quantified circulating and storage neutrophils, their precursors and progenitors, and mRNA for some of the cytokines involved in granulocytopoiesis, in newborn and adult mice following intrapulmonary inoculation of Escherichia coli. Four hours following inoculation of adult and newborn mice with a quantity of organisms 2 logs below the LD100, all animals were neutropenic. After 24 h, adults had recovered from the neutropenia but neonates had not (p < 0.001). Accelerated neutrophil production was evident in the infected adults, and correlated with the appearance of granulocyte colony-stimulating factor (G-CSF) transcripts in the liver, spleen, and lung, and interleukin-6 (IL-6) transcripts in the spleen and lung. An increase in neutrophil production was not observed in the neonates, and none of their organs tested had transcripts for either G-CSF or IL-6, but they did have transcripts for cytokines not involved in granulocytopoiesis; macrophage colony-stimulating factor and its receptor (c-fms). We speculate that the failure to increase neutrophil production in infected neonatal mice is the result of failure to increase production of relevant cytokines.
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PMID:The failure of newborn mice infected with Escherichia coli to accelerate neutrophil production correlates with their failure to increase transcripts for granulocyte colony-stimulating factor and interleukin-6. 750 13

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

Granulocyte colony-stimulating factor (G-CSF) is a hematopoietic growth factor produced by mesenchymal and myeloid cells following activation by inflammatory stimuli. It has previously been shown that a region of the G-CSF promoter, (-200 to -165) containing the decanucleotide CK-1 element and two repeated sequences that resemble nuclear factor (NF)-interleukin-6 (IL-6) binding sites, is required for activation of the G-CSF gene by tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta. We now show that the NF-kappa B p65 protein can bind to and activate this TNF response region. There are several unusual features of this p65 interaction with the TNF response region. First, NF-kappa B p65 but not the related NF-kappa B p50 binds to the CK-1 element and a p50/65 hybrid protein that relies on the p50 rel homology domain for DNA binding does not transactivate the TNF response region. Second, p65 transactivation of this region is cell specific and requires not only its own binding site but also the NF-IL6 consensus sites. NF-IL6 also binds to the TNF response region of the G-CSF promoter. Electrophoretic mobility shift studies show that p65 and NF-IL6 can bind cooperatively to the TNF response region. The ability of this region to respond to TNF-alpha or p65 is correlated with the ability to form the p65/NF-IL6 ternary complex.
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PMID:Requirement for nuclear factor (NF)-kappa B p65 and NF-interleukin-6 binding elements in the tumor necrosis factor response region of the granulocyte colony-stimulating factor promoter. 751 99

A number of recombinant cytokines believed to regulate normal hematopoiesis are now being used in cancer treatment protocols to reduce the myelosuppressive toxicity of intensive chemoradiotherapy regimens. It is widely assumed that such cytokines are relatively specific for hematopoietic cells, although some cell lines derived from a variety of non-hematopoietic human tumors can respond to some of these factors. However, relatively little is known about their ability to stimulate (or inhibit) the proliferation of freshly isolated normal or malignant non-hematopoietic cells. We have used a serum-free culture medium that selectively supports the growth of human breast epithelial cells (HBEC) obtained directly from normal or malignant tissue samples to evaluate potential stimulatory or inhibitory effects of eight cytokines: granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Steel factor, interleukin-2, interleukin-3, interleukin-6, transforming growth factor-beta and macrophage inflammatory protein-1 alpha, on these cells cultured both in the presence of epidermal growth factor, a potent stimulator of HBEC growth, and in its absence. HBEC growth was assessed after 7 and 14 days using the tetrazolium-dye reduction assay. Potential effects on the well studied MCF-7 breast cancer cell line, cultured under the same conditions, were also investigated. None of the cytokines (which were tested over a wide range of concentrations) had any modulating effect on the growth of normal or malignant HBEC under the conditions used with the exception of transforming growth factor-beta, which was consistently and significantly inhibitory.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of effect of hematopoietic growth factors on human breast epithelial cell growth in serum-free primary culture. 751 1

Colony-stimulating factors (CSFs) are proteins that play normal roles in human hematopoietic physiology. Many of these factors have been cloned and sequences. This has led to recombinant DNA technology that now allows for production of large quantities of pharmacologically pure compounds. Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are two such compounds that have been approved by the US Food and Drug Administration for human use in specific medical circumstances. This article summarizes the experience of one institution in using these two CSFs and adds brief commentary on four other CSFs that are expected to come to general use in the near future--interleukin-1, interleukin-3, interleukin-6, and erythropoietin. Both G-CSF and GM-CSF are effective in protecting patients from the leukotoxic effects of cancer chemotherapy, but GM-CSF appears to have a comparatively narrow "dosing window," wherein the agent is effective and tolerable. Future studies should address combining these agents with platelet protective compounds to improve patient safety.
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PMID:The use of colony-stimulating factors as bone marrow support for systemic anticancer chemotherapy. 752 98

Granulocyte colony-stimulating factor (G-CSF) is a glycoprotein that stimulates proliferation and differentiation of progenitor cells of neutrophils by signaling through its receptor (G-CSFR). Although the G-CSFR belongs to the cytokine receptor superfamily, which lacks an intracellular kinase domain, G-CSF-induced tyrosine phosphorylation of cellular proteins is critical for its biologic activities. We report here that JAK1 and JAK2 tyrosine kinases are tyrosine phosphorylated in response to G-CSF induction. We also demonstrate that the DNA-binding protein STAT3 (also called the acute-phase response factor [APRF], activated by interleukin-6) is an early target of G-CSF-induced tyrosine phosphorylation. G-CSF induces two DNA-binding complexes; the major complex contains tyrosine phosphorylated STAT3 protein and the minor complex appears to be a heterodimer of the STAT1 (previously p91, a component of DNA-binding complexes activated by interferons) and STAT3 proteins. Antiphosphotyrosine antibody interferes with the DNA binding activity of activated STAT3, indicating that tyrosine phosphorylation of STAT3 is important for the DNA binding activity. These results identify a signal transduction pathway activated in response to G-CSF and provide a mechanism for the rapid modulation of gene expression by G-CSF.
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PMID:Rapid activation of the STAT3 transcription factor by granulocyte colony-stimulating factor. 752 88


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