UNIPROT:P04141 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated a constitutive expression of transforming growth factor alpha (TGF-alpha) in normal human blood eosinophils, both at the mRNA and protein level. This may indicate a novel function of the eosinophil, the regulation of which has not been clarified. Therefore human white blood cells (WBC) were treated with potential regulators of eosinophil function. Northern blot analysis demonstrated that human recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-3 (IL-3) caused a time and dose-dependent 2- to 3-fold increase of TGF-alpha mRNA levels, in relation to incubation in the absence of cytokine; maximal response was attained within 4 h of incubation. In contrast, IL-5 failed to influence the expression of the TGF-alpha gene. In situ analysis of GM-CSF- or IL-3-stimulated cells showed that eosinophils remained the sole cell type expressing TGF-alpha mRNA. However, whereas GM-CSF significantly induced, within 1 h, release of immunoreactive TGF-alpha protein, IL-3 was insufficient in this respect. In conclusion, our findings indicate that expression of TGF-alpha gene and protein in normal blood eosinophils is differently regulated by GM-CSF and IL-3.
...
PMID:Transforming growth factor alpha expression in normal human blood eosinophils: differential regulation by granulocyte-macrophage colony-stimulating factor and interleukin-3. 751 73

To extent our knowledge on the cytokines possibly involved in the pathophysiology of B-cell chronic lymphocytic leukemia (B-CLL), the mRNA expression of a panel of 10 cytokines was investigated on purified B-CLL cells using a reverse-transcriptase polymerase chain reaction method. Whereas negative RT-PCR signals were recorded for interleukin-1 alpha (IL-1 alpha), IL-2, IL-3, IL-4, IL-5, IL-7, tumor necrosis factor beta (TNF beta), and granulocyte-macrophage colony-stimulating factor, we detected the expression of IL-1 beta, IL-6 and TNF alpha. Furthermore, the constitutive expression of IL-8 mRNA was observed in all 17 B-CLL samples analyzed. mRNA expression was associated with the capacity of the leukemic cells to release IL-8 both constitutively (4.6 +/- 8.1 SD ng/mL) and, to a further extent, after stimulation (14.5 +/- 19.4 ng/mL). The circulating levels of IL-8 were also evaluated in 12 untreated B-CLL sera samples and the overall mean level was significantly higher (P < .01) than in normal sera. In addition, supernatants of purified B-CLL cells cultured in the presence of 12-O-tetradecanoylphorbol-13-acetate showed chemotactic activity towards neutrophils; this activity was neutralized in the presence of an anti-IL-8 antiserum. The mRNA for IL-8 was absent in five B-cell preparations from hairy cell leukemia cases and in four B-cell lines. Normal tonsil CD5+ B cells showed a low expression of IL-8 mRNA only in two of the nine preparations tested and the overall quantity of IL-8 released by these cells after 3 days' incubation was significantly lower compared with that released by B-CLL cells (0.4 +/- 0.3 and 1.6 +/- 0.9 ng/mL under basal and stimulated conditions, respectively). These findings point to an involvement of a member of the proinflammatory chemokine supergene family in human CD5+ B lymphocytes. The different IL-8 behavior observed between B-CLL cells and their normal counterpart is likely to reflect an activation state of the leukemic population.
...
PMID:Cytokine gene expression in B-cell chronic lymphocytic leukemia: evidence of constitutive interleukin-8 (IL-8) mRNA expression and secretion of biologically active IL-8 protein. 751 9

Monocyte chemotactic and activating factor (MCAF) is the most potent cytokine that activates basophils to release histamine. The response of human basophils to either simultaneous or sequential addition of the chemokines RANTES, macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, platelet factor (PF)4, connective tissue activating peptide III (CTAP-III), interleukin (IL)-8, and inflammatory protein (IP)-10 on MCAF-induced histamine release was studied. Simultaneous addition of MCAF and any of the chemokines studied evoked an augmented response as measured by histamine release, whereas preincubation of leukocytes or purified basophils (80%) with these chemokines decreased MCAF-induced histamine release in a dose-dependent manner. Histamine release by anti-IgE remained unchanged. When tested at 5 x 10(-9) mol/L, the decrease in histamine release by RANTES was 69.2% +/- 3.5%, by MIP-1 alpha 48.8% +/- 3.1%, by MIP-1 beta 42.9% +/- 3.1%, by PF4 56.5% +/- 2.9%, by IL-8 41.2% +/- 2.2, by CTAP III 27% +/- 4.4%, and by IP-10 15.3% +/- 2.6%. The peak inhibition of histamine release by the chemokines was reached within 10 minutes of preincubation with basophils and remained unchanged thereafter. Washing basophils after preincubation with chemokines abolished the inhibition, with the exception of desensitization by low concentrations of MCAF. With the exclusion of MCAF and RANTES, none of the chemokines (at the concentration range of 5 x 10(-8) to 5 x 10(-11)) induced significant (> 10% above spontaneous) histamine release from basophils. Preincubation of basophils with C5a (5 x 10(-10) mol/L) did not affect histamine release, whereas preincubation with granulocyte-macrophage colony-stimulating factor (10 ng/ml) or IL-5 (10 ng/ml) enhanced MCAF-induced histamine release by 121.8% +/- 10.1% and 108% +/- 10.8%, respectively. We have therefore characterized RANTES, MIP-1 alpha, MIP-1 beta, CTAP III, PF4, IL-8, and IP-10 as inhibitors of MCAF-induced histamine release. Although the results are consistent with receptor blockade, the alpha and beta chemokines appear to interact with separate receptors linked to G proteins; thus, a mechanism of receptor class desensitization is proposed. Interaction of this group of cytokines at the site of allergic inflammation may modulate a function of basophils to initiate, augment, or inhibit histamine release.
...
PMID:Chemokines of the alpha, beta-subclass inhibit human basophils' responsiveness to monocyte chemotactic and activating factor/monocyte chemoattractant protein-1. 753 29

Development of small molecular mimics of larger polypeptide ligands is an important approach to pharmacophore design. One strategy for the development of such mimics is analysis of alternative ligands that bind to the same site as the native ligand. These allow examination of the structural and chemical constraints for binding within the setting of diverse backbone geometries. The use of antireceptor antibodies as alternative ligands has allowed the development of biologically active peptides in several ligand-receptor systems. This technology has been applied to the study of interactions between human granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor (GM-CSFR). GM-CSF is one of a family of signal-transducing cytokines and growth factors characterized by a four-helix bundle core structure. The GM-CSFR is comprised of an alpha-chain (GM-CSFR alpha) specific for GM-CSF, and a beta-chain (beta c) shared with the interleukin-3 and interleukin-5 receptors. At least two sites on GM-CSF have been implicated in the GM-CSF-GM-CSFR alpha/beta c ternary complex. In studies summarized here, synthetic peptide analogs of GM-CSF sequences were designed and used to map neutralizing epitopes. One neutralizing epitope corresponded to the A helix of GM-CSF, and a synthetic analog displayed biological activity as a GM-CSF antagonist in vitro, suggesting interaction with the GM-CSFR alpha/beta c complex. A second peptide comprising the B and C helices was recognized by monoclonal neutralizing antibodies and similarly displayed antagonist activity. Recombinant antibody (rAb) technology was also employed. An expression library of rAbs from mice immunized with neutralizing anti-GM-CSF antibodies was developed and screened with a neutralizing anti-GM-CSF monoclonal antibody. One clone which displayed receptor binding activity exhibited structural similarity with epitopes on GM-CSF previously implicated as interaction sites with the neutralizing monoclonal antibody. A synthetic peptide analog of the rAb inhibited GM-CSF bioactivity. Critical contact residues were predicted on the basis of structural similarity of the rAb peptide and GM-CSF. These studies indicate the feasibility of using rAbs in bioactive peptide design, providing lead compounds and information regarding contact residues for drug design.
...
PMID:Granulocyte-macrophage colony-stimulating factor mimicry and receptor interactions. 753 25

The effects of transforming growth factor (TGF) beta 1 on cytokine-enhanced eosinophil survival and degranulation were investigated in vitro to determine whether it is an inhibitory regulator of allergic inflammation. Peripheral blood eosinophils purified by Percoll density gradient centrifugation and the CD16 negative selection technique were incubated in the presence of eosinophil-activating cytokines (interleukin-5 (IL-5), IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-gamma) with and without TFG-beta 1 for 1-3 days. On day 1, eosinophil protein X release was measured by radioimmunoassay. Eosinophil viability on day 3 was determined by staining the cells with fluorescein diacetate and propidium iodide, and on the same day DNA was extracted and subjected to gel electrophoresis to test for fragmentation. TGF-beta 1 significantly inhibited eosinophil survival enhanced by IL-5, IL-3, GM-CSF and IFN-gamma in a dose-dependent manner. The inhibitory effects of TGF-beta 1 on IL-5-enhanced survival was partially reversed by high concentrations of IL-5 and was completely neutralized with anti-TGF-beta antibody. IL-5 inhibited DNA fragmentation of eosinophils in vitro. TGF-beta reversed the effect of IL-5, indicating that TGF-beta 1 activates the pathway of apoptosis. TGF-beta 1 significantly suppressed eosinophil protein X release induced by IL-5. These results suggest that TGF-beta 1 may play a role in the modulation of allergic inflammation.
...
PMID:Inhibitory effect of transforming growth factor beta 1 on cytokine-enhanced eosinophil survival and degranulation. 754 18

We have combined retroviral expression cloning with random mutagenesis to identify two activating point mutations in the common signal-transducing subunit (h beta c) of the receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-3 and IL-5 by virtue of their ability to confer factor independence on the haemopoietic cell line, FDC-P1. One mutation (V449E) is located within the transmembrane domain and, by analogy with a similar mutation in the neu oncogene, may act by inducing dimerization of h beta c. The other mutation (I374N) lies in the extracellular, membrane-proximal portion of h beta c. Neither of these mutants, nor a previously described mutant of h beta c (FI delta, which has a small duplication in the extracellular region), was capable of inducing factor independence in CTLL-2 cells, while only V449E could induce factor independence in BAF-B03 cells. These results imply that the extracellular and transmembrane mutations act by different mechanisms. Furthermore, they imply that the mutants, and hence also wild-type h beta c, interact with cell type-specific signalling molecules. Models are presented which illustrate how these mutations may act and predict some of the characteristics of the putative receptor-associated signalling molecules.
...
PMID:Activating point mutations in the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors suggest the involvement of beta subunit dimerization and cell type-specific molecules in signalling. 755 69

Gene targeting was used to create mice with a null mutation of the gene encoding the common beta subunit (beta C) of the granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3; multi-CSF), and interleukin 5 (IL-5) receptor complexes (beta C-/- mice). High-affinity binding of GM-CSF was abolished in beta C-/- bone marrow cells, while cells from heterozygous animals (beta C+/- mice) showed an intermediate number of high-affinity receptors. Binding of IL-3 was unaffected, confirming that the IL-3-specific beta chain remained intact. Eosinophil numbers in peripheral blood and bone marrow of beta C-/- animals were reduced, while other hematological parameters were normal. In clonal cultures of beta C-/- bone marrow cells, even high concentrations of GM-CSF and IL-5 failed to stimulate colony formation, but the cells exhibited normal quantitative responsiveness to stimulation by IL-3 and other growth factors. beta C-/- mice exhibited normal development and survived to young adult life, although they developed pulmonary peribronchovascular lymphoid infiltrates and areas resembling alveolar proteinosis. There was no detectable difference in the systemic clearance and distribution of GM-CSF between beta C-/- and wild-type littermates. The data establish that beta C is normally limiting for high-affinity binding of GM-CSF and demonstrate that systemic clearance of GM-CSF is not mediated via such high-affinity receptor complexes.
...
PMID:Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. 756 73

The concentrations of interleukin-5 (IL-5), granulocyte-macrophage colony-stimulating factor GM-CSF, and interleukin-3 (IL-3) in serum and in IL-2-stimulated lymphocyte culture medium (L-IL2-CM) prepared from patients with reactive eosinophilia were measured by enzyme-linked immunosorbent assay (ELISA). Serum IL-5 levels were increased in 16 out of 42 cases. GM-CSF and IL-3 were below the detectable levels in all sera examined. The concentrations of IL-5 and GM-CSF in L-IL2-CM were increased in 10 out of 29 patients. IL-3 was below the detectable levels in all L-IL2-CM.
...
PMID:Serum concentrations of IL-5, GM-CSF, and IL-3 and the production by lymphocytes in various eosinophilia. 757 7

Cytokines can stimulate eosinophils to produce cysteinyl leukotrienes (LTs) in the lung that provoke tissue destruction associated with asthma. Priming of an eosinophilic substrain of HL-60 cells (HL-60#7) with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) before ionophore challenge was found to produce an apparent 45% increase in total LT production in a dose-dependent manner (ED50 = 150 pmol/L) that could be accounted for by a decrease in the time required for maximal formation of LTs. GM-CSF had no effect on the kinetic parameters of LTC4 synthase and therefore probably acts upstream of this catalytic event. Incubation with interleukin-5 (IL-5), however, had no effect on LT biosynthesis. This differential priming ability was not a consequence of different receptor populations or differences in the affinity or stability of the ligand-receptor complexes of GM-CSF and IL-5. GM-CSF and IL-5 each displayed similar populations of high-affinity binding sites and neither GM-CSF nor IL-5 were able to cross-compete for the other's receptor binding sites. Analysis of phosphotyrosine patterns suggest that IL-5 is incapable of transducing a signal in eosinophilic HL-60#7 cells even though IL-5 and GM-CSF receptors mediate signal transduction via a common beta-chain component that is also necessary for high-affinity binding. Overall, this unique system may permit the dissection of distinct events responsible for specific intracellular signals transduced separately by GM-CSF or IL-5.
...
PMID:Differential activation of leukotriene biosynthesis by granulocyte-macrophage colony-stimulating factor and interleukin-5 in an eosinophilic substrain of HL-60 cells. 757 57

The amyloidogenic peptides, amyloid-beta (A beta) and human amylin, are the major constituents of amyloid deposits found in patients with the chronic degenerative disorders Alzheimer's disease (AD) and type 2 diabetes, respectively. Recent studies have shown that a variety of inflammatory proteins such as cytokines are associated with the amyloid deposits of AD brain tissues. Therefore, in the present study, we sought to determine whether A beta and/or human amylin could modulate the various inflammatory activities of eosinophils. We observed that human amylin but not A beta peptides inhibited the in vitro interleukin-5 (IL-5)-mediated survival of cord blood-derived eosinophils (CBEs) in a concentration-dependent manner. By contrast, rat amylin, a nonamyloidogenic peptide that is highly homologous to human amylin, failed to affect the IL-5-mediated survival of CBEs. Similar inhibitory effects of human amylin were observed for peripheral blood eosinophils. Human amylin also enhanced the release of the cytokine granulocyte-macrophage colony-stimulating factor by CBEs that were stimulated with the calcium ionophore A23187 but was incapable of directly stimulating CBEs to release cytokines. In addition, the A23187-induced release of the inflammatory lipid mediator leukotriene C4 by CBEs was augmented by human amylin. These results suggest that the amyloidogenic peptide human amylin is capable of amplifying the various inflammatory activities of eosinophils.
...
PMID:The amyloidogenic peptide human amylin augments the inflammatory activities of eosinophils. 759 53

<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>