Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of cytokines are found within foci of inflammation. Two of these cytokines, namely interleukin-1 (IL-1) and tumor necrosis factor (TNF), play a key role in orchestrating the mechanisms responsible for inflammation. These two cytokines induce production by many cells of lipid mediators, proteases, and free radicals, all of which play a direct role in development of the deleterious effects of inflammation. IL-1 and/or TNF exert cytotoxic effects on the vascular endothelium, cartilage, bone, muscle, or pancreatic beta-cell islets. Cytokines, including interferon gamma (IFN), IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), amplify the inflammatory response by increasing production of IL-1 and TNF by macrophages. Macrophages also produce other cytokines, such as IL-8 and macrophage chemoattractant protein-1 (MCP-1), with chemoattractant properties that contribute to draw leucocytes to the site of inflammation. IL-6, produced in large amounts during inflammatory processes, induces the production of acute phase proteins by hepatocytes. IL-1, TNF, IL-11, leukemia inhibitory factor (LIF), and transforming growth factor beta (TGF beta) share this effect. TGF beta also has a number of anti-inflammatory effects. TGF beta, IL-4, and IL-10 inhibit production of IL-1 and TNF. Glucocorticoids also have this effect. Glucocorticoids can be produced as a result of a chain of events initiated by IL-1, TNF, and IL-6 and involving the neuro-endocrine axis. Other substances, such as IL-1 receptor antagonist (IL-1 ra) or soluble forms of the TNF receptors, can specifically inhibit the effects of IL-1 and TNF. Cascade production of cytokines, inhibition, negative feed-back, and synergistic mechanisms are parameters that illustrate the concept of "cytokine network" and aptly characterize the role of these mediators in the mechanisms of inflammation.
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PMID:[Contribution of cytokines to inflammatory mechanisms]. 750 93

The human interleukin-3 (IL-3) receptor is constitutively expressed on certain hematopoietic cells where it mediates proliferation and differentiation, or functional activation. We have recently found that human umbilical vein endothelial cells (HUVECs) also express IL-3 receptors and that the expression is enhanced by stimulation with the monokine tumor necrosis factor alpha. In this report we show that the lymphokine interferon gamma (IFN gamma) is a powerful stimulator of the IL-3 receptor of HUVECs and that the combination of IL-3 and IFN gamma has a synergistic effect on major histocompatibility complex (MHC) class II expression and on the production of the early-acting hematopoietic cytokines IL-6 and granulocyte colony-stimulating factor (G-CSF). IFN gamma caused a time- and dose-dependent up-regulation of mRNA for both the alpha and beta chains of the IL-3 receptor, with maximal effects occurring 12 to 24 hours after stimulation with IFN gamma at 100 U/mL. Induction of mRNA correlated with protein expression on the cell surface, as judged by monoclonal antibody staining of both receptor chains and by the ability of HUVEC to specifically bind 125I-labeled IL-3 (125I-IL-3). Scatchard analysis of HUVECs stimulated with IFN gamma at 100 U/mL for 24 hours showed approximately 6,300 IL-3 receptors per cell that were of a high affinity class (dissociation constant [kd] = 500 pmol/L) only. The addition of IL-3 to IFN gamma-treated HUVECs strongly enhanced the expression of MHC class II antigen. Importantly, IFN gamma and IL-3 also exhibited a synergistic effect in the induction of the mRNA for G-CSF and IL-6. This was reflected in increased amounts of G-CSF and IL-6 protein in HUVEC supernatants. In contrast, IFN gamma and IL-3 did not stimulate granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-8 production in HUVECs. These results show that IFN gamma is a strong stimulator of IL-3 receptor expression in HUVECs and suggest that in vivo T-cell activation, causing the concomitant production of IFN gamma and IL-3, may lead to enhanced endothelial MHC class II expression and to the selective production of early-acting hematopoietic cytokines. Thus, IL-3 could influence immunity and hematopoiesis by acting not only on hematopoietic cells, but also on vascular endothelium.
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PMID:Interferon-gamma upregulates interleukin-3 (IL-3) receptor expression in human endothelial cells and synergizes with IL-3 in stimulating major histocompatibility complex class II expression and cytokine production. 754 Aug 83

HLA-identical bone marrow transplantation (BMT) is associated with both graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) reactivity. Different T-cell subsets from the bone marrow (BM) graft may be responsible for GVHD and GVL reactivity after BMT. In the etiology of GVHD, not only CD8+ but also CD4+ donor T lymphocytes may play an important role. Here we report a patient with chronic myeloid leukemia (CML) who was transplanted with the BM from his HLA-genotypically identical sister. After BMT there was complete engraftment, but the patient died because of acute GVHD grade III-IV in complete remission. Cytotoxic T-lymphocyte (CTL) lines were generated after BMT using the irradiated leukemic cells from the patient as stimulator cells and the donor-originated peripheral blood mononuclear cells, procured from the patient after BMT, as responder cells. The generated CTL lines showed specific lysis of the recipient lymphocytes and leukemic cells in a 51Cr release assay. Two types of CTL clones could be established from these CTL lines, both phenotypically CD4+. Clone type I showed male-specific HLA-DQ5-restricted lysis of the recipient lymphocytes, but not of the circulating relatively mature leukemic cells from the patient. This may be explained by the low HLA-DQ5 expression of the more mature CML cells. Clone type II showed HLA-DR2-restricted minor histocompatibility antigen-specific lysis of the recipient lymphocytes and leukemic cells. Both types of CTL clones showed antigen-specific cell-mediated growth inhibition of the recipient clonogenic leukemic precursor cells. These CD4+ CTL clones produced several activating cytokines including tumor necrosis factor alpha, interferon gamma, granulocyte-macrophage colony-stimulating factor (GM-CSF), and macrophage CSF. Our results illustrate that these CD4+ CTL clones may have induced GVHD directly by cytolysis and indirectly by activating cytokines. Because both types of CTL clones recognized the recipient leukemic progenitor cells, they may also contribute to GVL reactivity after BMT.
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PMID:Generation of CD4+ cytotoxic T-lymphocyte clones from a patient with severe graft-versus-host disease after allogeneic bone marrow transplantation: implications for graft-versus-leukemia reactivity. 767 Jan 18

To evaluate the effect of colony-stimulating factors and interferon gamma on the oxidative burst capacity of neutrophils in chronic granulomatous disease (CGD) we studied the neutrophils of a patient with variant CGD both from peripheral blood and from bone marrow culture on day 7 and 14. The results revealed that preincubation of peripheral neutrophils for 24 h in medium containing recombinant human granulocyte colony-stimulating factor (rhG-CSF), recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF), and recombinant human interferon gamma (rhIFN-gamma) alone or in combination did not improve the maximal oxidative burst activity measured by MTT assay. The colonies of this patient formed in agar assay were either composed of predominantly nitroblue tetrazolium (NBT)-positive cells or completely unable to reduce NBT. Despite variable colony numbers in the presence of different cytokines, the rate of NBT-positive colonies was less than 17% of the total number of colonies. However, more than 72% of the colonies were NBT positive in controls. In liquid culture, bone marrow cells yielded a comparable rate of NBT-positive and -negative populations at day 7. These data indicate that rhG-CSF, rhGM-CSF, and rhIFN-gamma alone or rhG-CSF and rhGM-CSF in combination with rhIFN-gamma are not able to reconstitute the oxidative burst defect in CGD in vitro. Indeed, regarding colony-forming capacity, the bone marrow cells from the patient responded to CSFs as well as those from control donors did. This fact may warrant the administration of hematopoietic growth factors, at least in variant CGD, in order to enhance the absolute number of functionally normal neutrophils.
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PMID:Clonal growth of functionally normal and deficient neutrophils from the bone marrow of a patient with variant chronic granulomatous disease. Lack of reconstitution of oxidative burst defect by G-CSF, GM-CSF, and IFN-gamma in vitro. 767 93

Signal transducers and activators of transcription (STAT proteins) bind to palindromic sequence elements related to interferon gamma (IFN-gamma) activation sites, which were first identified in the promoters of IFN-gamma-inducible genes. Although the sequences of the natural palindromic STAT-binding elements vary considerably, they conform to the general structure TT(N)5AA. We have systematically examined the effects of the spacing between the TT and AA core half sites on the binding of the STAT complexes activated by IFN-gamma, interleukin (IL) 6, granulocyte-macrophage colony-stimulating factor, and IL-4. We show that (i) as suggested earlier, a core palindromic TT--AA motif with a 5-bp spacing displays general STAT binding, (ii) a palindromic motif with a spacing of 4 bp selectively binds to complexes containing Stat3, and (iii) a motif with a 6-bp spacing selectively binds the STAT complexes activated by IL-4. We have examined natural elements in the promoters of cytokine-responsive genes that differ in half-site spacing and found that they display binding properties predicted from the synthetic binding sites. Furthermore, the observed differential selective binding characteristics for the most part correlate with the ability to mediate transcriptional activation of transfected test genes in response to the cytokines tested. Our results thus demonstrate that the specificity of STAT-directed transcription in response to particular cytokines or cytokine families depends in part on the spacing of half sites within the conserved response element sequence.
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PMID:Spacing of palindromic half sites as a determinant of selective STAT (signal transducers and activators of transcription) DNA binding and transcriptional activity. 770 71

Knowing how mycobacteria exploit host cytokines to survive and which cytokines have important roles in host defense against mycobacteria should allow the use of these molecules in the treatment of mycobacterial infections. Both interleukin 2 and interferon gamma have been used to treat patients with leprosy, and granulocyte-macrophage colony-stimulating factor is presently being administered to AIDS patients infected with Mycobacterium avium.
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PMID:Recombinant cytokines for controlling mycobacterial infections. 771 35

We have previously reported that neutrophilic granulocytes rapidly release part of their Fc gamma RIII from the plasma membrane upon in vitro activation, probably by proteolytic cleavage. In plasma and other body fluids, released or soluble Fc gamma RIII has been found in considerable amounts. In the present study, neutrophils were kept in maintenance culture for 18 to 24 hours. Forty percent of the neutrophils completely lost Fc gamma RIII, and the remainder of the cells showed a 60% decrease in Fc gamma RIII expression on their surface. Released Fc gamma RIII was detected in the culture supernatant. Nevertheless, more than 90% of the cells was viable as judged by hydrolysis of fluorescein diacetate. The presence of interferon gamma, granulocyte colony-stimulating factor, or granulocyte-macrophage colony-stimulating factor, but not interleukin-3 (IL-3), IL-6, or IL-8, in the culture medium increased the number of cells that still expressed Fc gamma RIII. We found that this loss of Fc gamma RIII was not the result of cell activation but correlated strongly with apoptosis. The Fc gamma RIII-negative subpopulation exhibited typical morphologic changes, such as nuclear condensation and DNA fragmentation. Furthermore, this subpopulation appeared to have acquired the property of binding Annexin V, a calcium-dependent, phospholipid-binding protein with high affinity for phosphatidylserine. The external exposure of this phospholipid by cells has been reported to occur during apoptosis. The property of Annexin V binding was not shared by the nonapoptotic, Fc gamma RIII-positive subpopulation. In this respect, we identified binding of Annexin V as an convenient marker for apoptotic cells. Our results indicate that soluble Fc gamma RIII in body fluids might be derived for a large part from neutrophils undergoing apoptosis in the tissues.
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PMID:Human neutrophils lose their surface Fc gamma RIII and acquire Annexin V binding sites during apoptosis in vitro. 781 8

The hematopoietic growth factors interleukin-3 (IL-3), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate the survival, maturation, and activation of eosinophils. Corticosteroids in contrast have a negative effect both on the hematopoietic process and the function of eosinophils. We have unexpectedly observed synergy between IL-5 and glucocorticoids such as dexamethasone and hydrocortisone for induction of the MHC class II antigens HLA-DR and HLA-DP on eosinophils isolated from human blood. Similarly glucocorticoids enhanced GM-CSF and IL-3, but not interferon gamma (IFN gamma), induced expression of these antigens. Expression of a third MHC class II molecule, HLA-DQ, was not induced on eosinophils by any of the cytokines alone, but in one of three donors tested, IL-3 plus dexamethasone induced high levels of expression. Although cytokine-induced expression of the accessory molecule intercellular adhesion molecule 1 (ICAM-1) was partially inhibited by glucocorticoids, cytokine- and dexamethasone-treated eosinophils presented antigen more efficiently to a hemagglutinin peptide-specific T-cell clone than eosinophils treated with cytokine alone. These results highlight a potential new role for endogenous or exogenous glucocorticoid hormones in enhancing MHC class II expression by eosinophils.
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PMID:Synergy between dexamethasone and interleukin-5 for the induction of major histocompatibility complex class II expression by human peripheral blood eosinophils. 791 86

Acute myelogenous leukemia (AML) cells express CD23 surface antigen after in vitro treatment with various cytokines, including interleukin-4 (IL-4) and interferon gamma. Subsequent ligation of CD23 by specific monoclonal antibody (MoAb) induces substantial morphologic and functional modifications in these cells. In the present study, we investigated the role of CD23 in the proliferation and the maturation of leukemic cells from AML patients or the U937 cell line. CD23+ cell treatment with CD23 MoAb inhibited the proliferation of leukemic cells. This correlated with their terminal differentiation after 7 to 9 days incubation because they (1) definitively lost their growth capacity; (2) adhered to culture flasks and became monocyte/macrophage-like; and (3) expressed mature monocyte markers including nonspecific esterases. Intracellular mechanism of this antitumoral effect was then analyzed in U937 cells. Induction of high-density surface CD23 expression by IL-4 or granulocyte-macrophage colony-stimulating factor coincided with a transient decrease of U937 cell proliferation. CD23 ligation during this low-proliferative phase induced a rapid activation of L-arginine-dependent pathway and the intracellular accumulation of cyclic guanosine monophosphate and cyclic adenosine monophosphate (cAMP). Induction of these early messengers was followed by the activation of nuclear factor-kB transcription factor and the modulation of proto-oncogene expression by U937 cells. Whereas U937 cell treatment with IL-4 decreased c-fos/c-jun expression, CD23 MoAb reinduced c-fos/c-jun and promoted the expression of cell maturation-associated proto-oncogenes junB and c-fms, during the first 24 hours. Both IL-4 and CD23 MoAb downregulated the expression of c-myb. CD23 ligation also induced the production of TNF alpha by U937 cells. Inhibitors of cAMP and nitric oxide reversed CD23-mediated modification in U937 cells. These data evidence the ability of CD23 surface antigen to mediate terminal differentiation of early leukemic myelomonocytic cells.
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PMID:Growth arrest and terminal differentiation of leukemic myelomonocytic cells induced through ligation of surface CD23 antigen. 794 82

Expression of lymphokine genes including interleukin 2 (IL-2), interleukin 3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma (IFN-g), tumor necrosis factor (TNF) and lymphotoxin (LT) were sequentially monitored in peripheral blood mononuclear cells by Northern blot analysis after stimulation with phytohemagglutinin (PHA). The pattern of the expression of lymphokine genes following PHA stimulation as categorized into two types. Type 1 was characterized by rapid appearance of mRNA and by early maximum accumulation. Type 2 was characterized by the prolonged expression and late peak time. Lymphokines including IL-2, IL-3 and GM-CSF belong to type 1 and IFN-g, TNF and LT belong to type 2. Since lymphokines in type 1 are known to act on hematopoiesis in a stimulatory manner, whereas type 2 show an inhibitory action, this sequential expression of lymphokines following mitogen stimulation may reflect some biological feedback mechanism.
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PMID:Sequential expression of lymphokine genes during phytohemagglutinin-stimulated mitogenesis of normal human peripheral mononuclear cells. 801 27


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