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)

Human mast cells are multifunctional tissue-dwelling cells that play a crucial role in eosinophil-dependent disorders, such as asthma and parasitic diseases, by the secretion of eosinophil-active mediators. Mast cell-derived cytokines, generated in response to cross-linking of the high-affinity IgE receptor, can regulate eosinophil activation, survival, and chemotaxis. In this study, mast cells generated from human cord blood progenitors (stem cells) were studied for eosinophil-active inflammatory cytokine expression. Cord blood-derived mast cells (CBDMC) expressed typical intracellular scroll granules and microvilli-like structures on their cell surfaces, demonstrated the presence of tryptase, and elaborated prostaglandin D2 (PGD2) after cross-linkage of the high-affinity receptor for IgE (FcepsilonRI). CBDMC expressed tumor necrosis factor-alpha (TNF-alpha) and the eosinophil-active growth factors, interleukin-5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) after activation. (IL-1beta greatly enhanced IgE-dependent production of these cytokines in response to FcepsilonRI cross-linkage, suggesting a role for bystander/phagocytic cells in modulating mast cell function. In contrast, interferon-alpha (IFN-alpha) inhibited IL-5 and GM-CSF generation, and the glucocorticoid, dexamethasone (Dex), inhibited production of IL-5 and GM-CSF from CBDMC. A macrophage-mast cell-eosinophil axis may exist in vivo that may be susceptible to pharmacologic manipulation.
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PMID:Regulation of eosinophil-active cytokine production from human cord blood-derived mast cells. 1203 46

The ability of interferon-alpha (IFN-alpha) to induce dendritic cell (DC) differentiation in chronic myeloid leukemia (CML) was evaluated. Peripheral blood mononuclear cells from CML patients cultured with IFN-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) developed a dendritic morphology. Fluorescence in situ hybridization demonstrated that the DCs harbored the bcr/abl translocation. The DCs prepared with IFN-alpha/GM-CSF expressed significantly higher levels of class I and II HLA than those grown in interleukin-4 (IL-4) and GM-CSF. The DCs prepared from newly diagnosed CML patients using IFN-alpha/GM-CSF expressed immunoregulatory proteins at levels comparable to normal DCs. In contrast, DCs cultured from CML patients who did not achieve a cytogenetic response to IFN-alpha expressed significantly lower levels of class I HLA, CD40, CD54, CD80 and CD86 than normal DCs. The expression of CD86 by CML DCs was enhanced when they were cultured with IFN-alpha/IL-4/GM-CSF, or when IFN-alpha/GM-CSF-treated cells were induced to mature by CD40 ligand. The DCs from IFN-alpha failures were less stimulatory than normal DCs in the allogeneic mixed leukocyte reaction. CML patients who had a cytogenetic response to IFN-alpha initially had low numbers of bone marrow DCs that increased significantly with treatment, while nonresponders had more prevalent DCs at baseline that showed no consistent change with treatment. Therefore, IFN-alpha can induce DC differentiation from CML progenitor cells both in vitro and in vivo. The therapeutic activity of IFN-alpha in CML may be due to its ability to stimulate the generation of DCs that can present CML-specific antigens. Resistance to IFN-alpha may result when DC differentiation becomes impaired.
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PMID:Interferon-alpha induces dendritic cell differentiation of CML mononuclear cells in vitro and in vivo. 1275 Jul 16

The principal interferon-alpha/beta (IFN-I)-producing cells are plasmacytoid dendritic cell (PDC) precursors belonging to the lymphoid lineage. Monocytes that can differentiate into dendritic cells (DC) also produce IFN-I, although much less than PDC, after interaction with infectious agents. We show that whereas viruses trigger these cells to produce IFN-I, the amount of IFN is tightly controlled by cytokines. Monocytes produced IFN-I in response to Sendai virus (SV) infection, and PDC responded to both SV and herpes simplex virus (HSV). All cytokines tested failed to induce production of IFN-I in the absence of infection. However, among 18 relevant cytokines, incubation of PDC with interleukin-4 (IL-4), IL-15, and IL-7 alone or in combination with IL-3 before infection, enhanced IFN-I secretion. At variance, IL-12 alone or in synergy with granulocyte-macrophage colony-stimulating factor (GM-CSF) was active on SV-infected but not on HSV-infected monocytes. Tumor necrosis factor-alpha (TNF-alpha) and IL-4 inhibited IFN-I production by PDC and monocytes, respectively, and IL-10 strongly inhibited IFN-I production in both cell lineages. The response of PDC to IL-7 and IL-15, which also activate natural killer (NK) cell maturation, further emphasizes the cooperation between these two cell subsets in the control of innate immunity.
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PMID:Type I interferon production by plasmacytoid dendritic cells and monocytes is triggered by viruses, but the level of production is controlled by distinct cytokines. 1216 75

Cyclophosphamide, interferon-alpha and betamethasone are all effective agents for the treatment of multiple myeloma (MM) with different mechanisms of action. The clinical effect of a combination of cyclophosphamide 725 mg/m(2) i.v. days 1 and 3, interferon-alpha 7 x 10(6) IE/m(2) s.c./day, days 1-4 and betamethasone 30 mg orally days 1-4 (CIB) was studied in patients aged 60-75 years with previously untreated MM stages II and III. Granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 microg/kg/day s.c. was administered to all patients from day 5 until the day the granulocyte count exceeded 1.0 x 10(9)/l. CIB was repeated every fourth week. Interferon-alpha 3 x 10(6) IE s.c. t.i.w. was given as maintenance therapy in responding patients.A total of 28 patients (median age: 67 years) entered the study. In all, 12 patients had stage II and 16 had stage III MM. A total of 22 patients (79%) showed an objective response, including five complete remissions (CR) and 17 partial remissions (PR). All seven patients with Bence-Jones MM responded (five CR and two PR). The median response duration time was 14 months (range 5-38+). CIB was relatively well tolerated although febrile neutropenia or septicaemia occurred in 5% of the cycles and a dose-reduction of cyclophosphamide due to grade IV neutropenia was performed in 11% of the patients.CIB seems to be an effective regimen for remission induction in MM patients aged up to 75 years as an alternative to VAD (vincristine, doxorubicin, dexamethasone) if a regimen with intensity higher than that of oral melphalan/prednisone is warranted.
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PMID:Phase II study of cyclophosphamide, interferon-alpha and betamethasone (CIB) as induction therapy for patients 60-75 years of age with multiple myeloma stages II and III. 1287 49

Dendritic cells (DC) can be derived from monocytes in vitro by culture with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). It is unknown whether this regimen reflects DC differentiation from blood precursors under physiological conditions. Induction of DC development from monocytes by interferon-alpha (IFN-alpha) may occur in vivo during infection or inflammation and thus may represent a more physiological approach to DC differentiation in vitro. Here, we show that incubation of GM-CSF-cultured monocytes with IFN-alpha does not induce DC differentiation: cells maintain their original phenotype and cytokine secretion pattern. Even after stimulation with pro-inflammatory or T-cell-derived activation signals, IFN-alpha-treated monocytes do not develop DC characteristics. Addition of IL-4 during stimulation of IFN-alpha-treated monocytes results in the rapid development of DC-like cells expressing co-stimulatory molecules, CD83 and chemokine receptor CCR7, indicating that some degree of developmental plasticity is preserved. However, DC pre-activated with IFN-alpha are less effective in inducing allogeneic or antigen-specific autologous T-cell proliferation, produce less IL-12 and express lower levels of CCR7 compared to DC generated by culture with GM-CSF and IL-4. Incubating GM-CSF-cultured monocytes simultaneously with IFN-alpha and IL-4 does not affect phenotypic maturation of DC, but reduces IL-12 production upon pro-inflammatory activation. We conclude that: (1) IFN-alpha fails to induce DC differentiation and thus cannot replace IL-4 in generating DC from monocytes in vitro; and (2) the presence of IFN-alpha prior to or during differentiation of DC from monocyte precursors alters their response to maturation stimuli and may affect their capacity to stimulate T helper type 1 immune responses in vivo.
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PMID:Interferon-alpha disables dendritic cell precursors: dendritic cells derived from interferon-alpha-treated monocytes are defective in maturation and T-cell stimulation. 1294 Nov 39

Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease arising from the clonal expansion of a stem cell expressing the bcr/abl oncogene. CML patients frequently respond to treatment with interferon-alpha (IFN-alpha), even though the mechanisms of the response remain unclear. In the present study, we evaluated the role of IFN-alpha in differentiation and activity of monocyte-derived dendritic cells (DCs) from CML patients as well as in modulation of the cell response to lipopolysaccharide (LPS). Treatment of CML monocytes with IFN-alpha and granulocyte-macrophage colony-stimulating factor (GM-CSF) resulted in the rapid generation of activated DCs (CML-IFN-DCs) expressing interleukin-15 (IL-15) and the antiapoptotic bcl-2 gene. These cells were fully competent to induce IFN-gamma production by cocultured autologous T lymphocytes and expansion of CD8(+) T cells. LPS treatment of CML-IFN-DCs, but not of immature DCs generated in the presence of IL-4/GM-CSF, induced the generation of CD8(+) T cells reactive against autologous leukemic CD34(+) cells. Altogether, these results suggest that (1) the generation of highly active monocyte-derived DCs could be important for the induction of an antitumor response in IFN-treated CML patients and (2) IFN-alpha can represent a valuable cytokine for the rapid generation of active monocyte-derived DCs to be utilized for vaccination strategies of CML patients.
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PMID:IFN-alpha promotes the rapid differentiation of monocytes from patients with chronic myeloid leukemia into activated dendritic cells tuned to undergo full maturation after LPS treatment. 1452 81

There is a growing interest in generating dendritic cells (DCs) for using as vaccines. Several cytokines, especially stem cell factor (SCF) and FLT3-ligand (FL), have been identified as essential to produce large numbers of myeloid precursors and even to increase DC yield obtained by the action of granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor alpha (TNF-alpha). However, there are few studies on the effect of the early-acting cytokines, commonly used to expand CD34+ progenitor cells, on DC generation. We report here that in the absence of serum, SCF, FL, and thrombopoietin (TPO) plus interleukin-6 (IL-6) and SCF, FL, and TPO plus IL-3 were able to generate CD14+CD1a- and CD14- CD1a+ myeloid DC precursors from CD34+ cells, but IL-6 had an inhibitory effect on the generation of CD14- CD1a+ cells. Both DC precursors differentiated into mature DCs by GM-CSF, IL-4, and TNF-alpha, and DCs obtained from both types of culture exhibited equal allostimulatory capacity. CD1a+ DCs generated could be identified on the basis of DC-specific intracellular adhesion molecule-grabbing nonintegrin (DC-SIGN) expression, a novel C-type lectin receptor expressed on dermal DCs but not on Langerhans cells. In addition, the inclusion of IL-3 to the culture medium induced the appearance of CD13- cells that differentiated into plasmacytoid DC (DC2) on the addition of TNF-alpha, allowing the identification of developmental stages of DC2. Like true plasmacytoid DCs, these cells secreted interferon-alpha after TLR9-specific stimulation with a specific CpG nucleotide.
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PMID:Selective generation of different dendritic cell precursors from CD34+ cells by interleukin-6 and interleukin-3. 1534 37

Adoptive immunotherapy with transfusion of donor lymphocytes in allogeneic stem cell chimeras has been successful in the treatment of recurrent chronic myelogenous leukaemia (CML) and some patients with acute myeloid leukaemia (AML). The hypothesis that the graft-vs-leukaemia effect (GVL) is promoted by leukaemia-derived dendritic cells has been supported by the concurrent treatment of patients with cytokines that are known to induce differentiation of leukaemia cells towards dendritic cells. In combination with donor lymphocyte transfusions, treatment with interferon-alpha and granulocyte-macrophage colony-stimulating factor has been studied in patients with recurrent CML and AML, and pre-emptively in patients with high-risk AML. Long-term remissions have been observed in cytokine-treated patients, indicating the beneficial effect of cytokine stimulation of GVL reactions. This is likely to be due to differentiation of leukaemia progenitor cells towards dendritic cells in vivo.
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PMID:In-vivo generation of leukaemia-derived dendritic cells. 1549 15

Hypereosinophilic syndrome (HES) is a rare disorder that is characterized by persistent and marked eosinophilia combined with organ system dysfunction. HES has substantial clinical heterogeneity but can be fatal without treatment, especially in patients who present with a myelodysplastic variant of the disorder. Although the pathophysiology of HES is poorly defined, dysregulation of cytokines (interleukin 5 [IL-5], IL-3, granulocyte-macrophage colony-stimulating factor [GM-CSF]) responsible for the maturation of eosinophils is a primary feature. Of these cytokines, IL-5 appears to have the greatest role in the regulation of eosinophil maturation. There is no Food and Drug Administration-approved treatment for HES as yet; current strategies are designed to lower blood eosinophils and attempt to limit end-organ damage. Historically, corticosteroids and cytotoxic agents have been the mainstays of therapy, with biological response modifiers such as interferon-alpha also effective in some patients. However, despite improvements in survival, available agents have significant limitations in terms of efficacy, tolerability, and long-term toxicity. More recently, new agents directed at specific targets in the pathogenesis of HES have been developed. These include imatinib mesylate, a tyrosine kinase inhibitor, and more recently, mepolizumab, an anti-IL-5 monoclonal antibody. In a small case series of patients, these agents have been shown to produce hematological and clinical responses in patients with HES, although they may be effective in different subsets of patients. These targeted therapies have the potential to improve clinical outcomes and to further the understanding the pathophysiology of this difficult-to-treat condition.
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PMID:Hypereosinophilic syndrome: an update. 1618 89

Cytokines are polypeptides that are produced by various cell types and act in an autocrine or paracrine manner. They have many different biological actions and have been used in dermatology to treat a wide range of dermatologic diseases. In this paper we review some of the more commonly used cytokines in dermatology, including interferon-alpha and -gamma, interleukins-2 and -10, and granulocyte-macrophage colony-stimulating factor. We specifically examine their roles in the treatment of condyloma and verruca, hemangiomas, keloids, skin cancers, atopic dermatitis, psoriasis, Behcet disease, chronic granulomatous disease, wound healing, and cutaneous T cell lymphoma. In addition, some of the adverse effects associated with these cytokines are discussed.
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PMID:Cytokines in dermatology. 1677 3


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