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)

Prolonged eosinophil survival is an essential step in the late and chronic phases of allergic inflammation and is regulated by the eosinophil survival cytokines. Our work has demonstrated that tumour necrosis factor (TNF)-alpha enhances survival (Trypan blue exclusion test) of human peripheral blood eosinophils from mildly allergic patients in a dose-dependent manner. The survival activity of TNF-alpha was inhibited by anti-TNF-RI, anti-TNF-RII antagonist antibodies and anti-granulocyte-monocyte colony-stimulating factor (GM-CSF) neutralizing antibodies but not by anti-interleukin (IL)-3 or anti-IL-5 antibodies. Furthermore, TNF-alpha-induced GM-CSF release from eosinophils. Anti-TNF-alpha antibodies also inhibited GM-CSF release from eosinophils induced by rat mast cell sonicate, which enhances eosinophil survival. To define the signal transduction pathway involved in GM-CSF production, eosinophils were incubated either with various mitogen-activated protein kinases (MAPK) inhibitors (MEK, JNK, P38), or Cyclosporin A (calcineurin inhibitor), or MG-132 (proteasome inhibitor). Only the proteasome inhibitor significantly decreased both TNF-alpha-enhanced eosinophil survival (from 38.1+/-4.1% to 13.3+/-1.4%) and GM-CSF release (from 6.2+/-0.7 pg/ml to 0.3+/-0.1 pg/ml). TNF-alpha also induced nuclear factor-kappaB (NF-kappaB) translocation to the nucleus, an essential step in GM-CSF mRNA production. All these findings provide evidence that NF-kappaB is involved in TNF-alpha-enhanced eosinophil survival through the regulation of GM-CSF production by eosinophils.
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PMID:Mechanism of tumour necrosis factor alpha mediated eosinophil survival. 1150 5

Oxidized LDL (oxLDL) is known to induce endothelial adhesion molecule and monocyte chemoattractant protein 1 expression and this is thought to be involved in monocyte recruitment into atherosclerotic lesions. oxLDL has also been found to induce macrophage proliferation. The purpose of the present study was to determine whether oxLDL might also have the ability to increase macrophage populations by inhibiting apoptosis. We found that oxLDL caused a dose-dependent inhibition of the apoptosis that occurs in cultured bone marrow-derived macrophages after macrophage colony-stimulating factor (M-CSF) withdrawal without inducing proliferation. Incubation of macrophages with either native LDL or acetylated LDL had no effect on apoptosis. The prosurvival effect of oxLDL was not inhibited by neutralizing antibodies to granulocyte-macrophage colony-stimulating factor, was maintained in mice homozygous for a mutation in the M-CSF gene, and was not due to other secreted cytokines or growth factors. oxLDL caused activation of the mitogen-activated protein kinases ERK1/2 (extracellular signal-regulated kinases 1 and 2) as well as protein kinase B (PKB), a target of phosphatidylinositol 3-kinase (PI 3-kinase). Furthermore, there was phosphorylation of two important prosurvival PKB targets, I-kappaBalpha(Ser-32) and Bad(Ser-136). The MEK inhibitors PD 98059 and U0126 blocked ERK1/2 activation but did not diminish survival. Conversely, the PI 3-kinase inhibitors LY 294002 and wortmannin blocked PKB activation, and the ability of oxidized LDL to promote macrophage survival. Taken together, these results indicate that oxLDL can directly activate a PI 3-kinase/PKB-dependent pathway that permits macrophage survival in the absence of growth factors.
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PMID:Oxidized low density lipoprotein inhibits macrophage apoptosis through activation of the PI 3-kinase/PKB pathway. 1151 69

Juvenile myelomonocytic leukemia (JMML) is an aggressive childhood disorder with few therapeutic options. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF-alpha) promote JMML cell growth. A hyperactive function of the ras oncogene is a hallmark of JMML. We therefore targeted the protein kinase Raf-1 downstream of Ras using a DNA enzyme that degrades mRNA-Raf-1. Western blots of JMML cell lysates revealed phosphorylated Raf-1 protein, indicating constitutive activation. Addition of GM-CSF, but not TNF-alpha, increased phosphorylation of both Raf-1 and the mitogen-activated protein kinases (MAPKs) JNK-1 and ERK-1. Depletion of Raf-1 protein markedly impaired activation of MAPKs, induced substantial inhibition of JMML cell colony formation, and virtually abolished GM-CSF hypersensitivity in JMML cells. Exogenous TNF-alpha, but not GM-CSF, restored colony formation of JMML cells pretreated with the enzyme. We could not detect any effect of the enzyme on the proliferation of normal bone marrow cells, indicating its specificity and potential safety. When immunodeficient mice engrafted with JMML cells were treated continuously with the enzyme via a peritoneal osmotic mini-pump for 4 weeks, a profound reduction in the JMML cell numbers in the recipient murine bone marrows was found. We conclude that GM-CSF is a chief regulator of JMML growth and exerts its proleukemic effects primarily via the Ras/Raf-1 signaling cascade. TNF-alpha plays a permissive role, being dependent upon GM-CSF to induce JMML cell proliferation. The DNA enzyme efficiently catabolized mRNA-Raf-1 with subsequent inhibition of JMML cell growth, suggesting its potential as a mechanism-based therapy in this fatal leukemia.
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PMID:Targeting Raf-1 gene expression by a DNA enzyme inhibits juvenile myelomonocytic leukemia cell growth. 1201 Aug 19

Human neutrophils are rescued from apoptosis following incubation with once-washed, fibroblast-derived Toxoplasma gondii tachyzoites. Both infected and uninfected neutrophils are rescued, implicating a soluble mediator. In this study we investigated the origin and identity of this soluble mediator. Neutrophils were incubated either with purified tachyzoites or with conditioned medium derived from T. gondii-infected human fibroblasts. Conditioned medium was found to be a potent stimulus that delayed neutrophil apoptosis up to 72 h, whereas purified and extensively washed tachyzoites had no effect. Delayed apoptosis correlated with up-regulation of the neutrophil antiapoptotic protein, Mcl-1, and the neutrophil interleukin 3 receptor alpha subunit (IL-3Ralpha), suggesting a role for granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF and granulocyte colony-stimulating factor (G-CSF) were measurable in conditioned medium by enzyme-linked immunosorbent assay. Neutralizing antibodies to GM-CSF and G-CSF were additive in abrogating delayed neutrophil apoptosis induced by conditioned medium. Inhibitors of Src family tyrosine kinases, G(i) proteins, phosphatidylinositol 3-kinase, p44(erk1) and p42(erk2) mitogen-activated protein kinases, and Jak2 kinases partially attenuated the effect of conditioned medium, consistent with a role for G-CSF and/or GM-CSF. Hence, delayed neutrophil apoptosis is mediated by GM-CSF and G-CSF secreted by T. gondii-infected human fibroblasts. This enhanced neutrophil survival may contribute to the robust proinflammatory response elicited in the T. gondii-infected host.
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PMID:Toxoplasma gondii induces granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor secretion by human fibroblasts: implications for neutrophil apoptosis. 1237 81

AU-rich elements (AREs) control the expression of numerous genes by accelerating the decay of their mRNAs. Rapid decay and deadenylation of beta-globin mRNA containing AU-rich 3' untranslated regions of the chemoattractant cytokine interleukin-8 (IL-8) are strongly attenuated by activating the p38 mitogen-activated protein (MAP) kinase/MAP kinase-activated protein kinase 2 (MK2) pathway. Further evidence for a crucial role of the poly(A) tail is provided by the loss of destabilization and kinase-induced stabilization in ARE RNAs expressed as nonadenylated forms by introducing a histone stem-loop sequence. The minimal regulatory element in the IL-8 mRNA is located in a 60-nucleotide evolutionarily conserved sequence with a structurally and functionally bipartite character: a core domain with four AUUUA motifs and limited destabilizing function on its own and an auxiliary domain that markedly enhances destabilization exerted by the core domain and thus is essential for the rapid removal of RNA targets. A similar bipartite structure and function are observed for the granulocyte-macrophage colony-stimulating factor (GM-CSF) ARE. Stabilization in response to p38/MK2 activation is seen with the core domain alone and also after mutation of the AUUUA motifs in the complete IL-8 ARE. Stabilization by ARE binding protein HuR requires different sequence elements. Binding but no stabilization is observed with the IL-8 ARE. Responsiveness to HuR is gained by exchanging the auxiliary domain of the IL-8 ARE with that of GM-CSF or with a domain of the c-fos ARE, which results in even stronger responsiveness. These results show that distinct ARE domains differ in function with regard to destabilization, stabilization by p38/MK2 activation, and stabilization by HuR.
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PMID:Distinct domains of AU-rich elements exert different functions in mRNA destabilization and stabilization by p38 mitogen-activated protein kinase or HuR. 1514 77

Thioredoxin truncated at its carboxy terminal (Trx80) acts as a cytokine that stimulates monocytes and eosinophils. In the present study, Trx80 was shown to induce differentiation of human CD14(+) monocytes into a cell type not described previously, which we designate as Trx80-activated monocytes (TAMs). TAMs resemble immature dendritic cells (iDCs) generated in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 4 (IL-4) in that both these cell populations exhibit increased proportions of CD1a(+) and mannose receptor (MR)(+) cells. However, in contrast to iDCs, TAMs express high proportion of CD14 and lower proportion of CD83 and HLA-DR. Functional assays revealed that, in comparison to iDCs, TAMs 1) exhibit a higher pinocytic capacity; 2) release significantly higher amounts of the proinflammatory cytokines tumor necrosis factor-alpha (TNF alpha), IL-1 beta, and IL-6 and of the anti-inflammatory cytokine IL-10; and 3) induce a significantly lower proliferative response in allogeneic peripheral blood mononuclear cells (PBMCs). Indeed, Trx80 appears to be the first endogenous substance shown to have the capacity on its own to induce IL-10 production by monocytes. Analysis of the mitogen-activated protein (MAP) kinase signaling pathway revealed that Trx80 induces phosphorylation of p38, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). We propose that Trx80 is an early signal in response to danger, and that TAMs may play a major role in triggering innate immune responses.
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PMID:Truncated thioredoxin (Trx80) induces differentiation of human CD14+ monocytes into a novel cell type (TAMs) via activation of the MAP kinases p38, ERK, and JNK. 1549 31

HIV-1-infected monocyte/macrophages located in lymph nodes and tissues are highly productive sources of HIV-1 and may function as a persistent reservoir contributing to the rebound viremia observed after highly active antiretroviral therapy is stopped. Mechanisms activating latently infected, primary monocyte/macrophages to produce HIV-1 were investigated using monocytes isolated from a transgenic mouse line carrying a full-length proviral clone of a monocyte-tropic HIV-1 isolate, HIV-1(JR-CSF), regulated by the endogenous long terminal repeat (LTR) (JR-CSF mice). Granulocyte-macrophage colony-stimulating factor (GM-CSF) combined with lipopolysaccharide (LPS) induced infectious HIV-1 production by JR-CSF mouse monocytes over 10-fold and 100-fold higher than that stimulated by GM-CSF or LPS alone, respectively. We examined mechanisms of GM-CSF synergy with LPS and demonstrated that GM-CSF up-regulated the LPS receptor, TLR-4, and also synergized with LPS to activate mitogen-activated protein (MAP) kinase/ERK kinase and the Sp1 transcription factor. Inhibitors of either MAP kinase/ERK kinase or p38 kinase but not PI 3-kinase potently suppressed GM-CSF and LPS-induced HIV-1 production by JR-CSF mouse monocytes. Because Sp1 is activated by both the MAP kinase/ERK kinase and p38 kinase pathways, we postulate that synergistic activation of these pathways by GM-CSF and LPS induced sufficient levels of Sp1 to activate the HIV-1 LTR in a Tat-independent manner and induced HIV-1 production by JR-CSF mouse monocytes. Thus, our study delineated the pathway of HIV-1 LTR activation by GM-CSF and LPS and indicated that JR-CSF transgenic mice may provide a new in vitro and in vivo system for investigating the mechanism by which inflammatory and infectious stimuli activate HIV-1 production from latently infected monocytes.
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PMID:Identification of granulocyte-macrophage colony-stimulating factor and lipopolysaccharide-induced signal transduction pathways that synergize to stimulate HIV type 1 production by monocytes from HIV type 1 transgenic mice. 1572 51

The reactivity of endothelial cells (ECs) to proinflammatory cytokines is critically important for the pathogenesis of vascular diseases. Here, we studied functional alterations of human ECs during culture under a confluent condition; i.e., the alterations of neutrophil-activating activity, platelet-activating factor (PAF) synthesis, and granulocyte-macrophage colony-stimulating factor (GM-CSF) production in cytokine-stimulated ECs. Human umbilical vein-derived ECs exhibited the increased activity in neutrophil activation, PAF synthesis, and GM-CSF production when stimulated by proinflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha). The activity of cytokine-stimulated ECs to stimulate superoxide release in human neutrophils and to produce PAF declined markedly in parallel as ECs became growth-arrested during culture under a confluent condition. By contrast, GM-CSF production induced by cytokine stimulation was modestly increased, and up-regulation of intercellular adhesion molecule-1 (ICAM-1) and activation of mitogen-activated protein kinases were not altered. The neutrophil-activating activity of cytokine-stimulated ECs was dependent on PAF synthesis and GM-CSF production from ECs. These findings indicate that the reduced neutrophil-activating activity in growth-arrested ECs may be, at least in part, ascribed to down-regulation of PAF synthesis.
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PMID:Neutrophil-activating activity and platelet-activating factor synthesis in cytokine-stimulated endothelial cells: reduced activity in growth-arrested cells. 1702 41

Various functions of mature human neutrophils are activated or potentiated by hematopoietic growth factors or proinflammatory cytokines such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and interleukin 1beta. The major signaling pathways activated in human neutrophils stimulated by proinflammatory cytokines include mitogen-activated protein kinases, Janus kinase/signal transducer and activator of transcription, phosphatidylinositol 3-kinase, and nuclear factor kappaB. These signaling pathways are involved in cytokine-mediated regulation of neutrophil functions in a cytokine-specific manner.
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PMID:Regulation of neutrophil functions by proinflammatory cytokines. 1705 Jan 92

The interleukin 4 (IL-4)/IL-4 receptor (IL-4R) system in promyelocytes is not well documented. Here, we used promyelocytic leukaemia PLB-985 cells differentiated with dimethylsulfoxide (PLB-985D) toward neutrophil-like phenotype to investigate the IL-4/IL-4R system. PLB-985 cells did not express CD132 (gammac) but expressed the complete IL-4 type II receptor (IL-4Ralpha and IL-13Ralpha1). Moreover, PLB-985 cells lost surface expression of IL-13Ralpha1 during differentiation, resulting in PLB-985D cells expressing only IL-4Ralpha fully responsive to IL-4, as judged by activation of mitogen-activated protein (MAP) kinases and Janus kinase 1. IL-4 also increased suppressor of cytokine signalling 3 (SOCS3) protein level in the presence of the proteasome inhibitor MG132 exclusively in PLB-985D cells. As the IL-4Ralpha chain has been associated with a component of the phagocyte NADPH oxidase, we used PLB-985-gp91(phox) deficient cells (mimicking chronic granulomatous disease, X-CGD), to investigate the IL-4/IL-4R system in X-CGD-D cells. IL-4 was found to activate MAP kinases in X-CGD-D cells but did not up-regulate SOCS3, in contrast to granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and IL-6. Utilization of catalase, cycloheximide and genistein inhibitors showed that IL-4 induced SOCS3 by a mechanism dependent on a complete NADPH oxidase complex, protein synthesis and tyrosine phosphorylation, but independent of production of reactive oxygen species. We conclude that IL-4 induces cell signalling in promyelocytes expressing only IL-4Ralpha.
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PMID:Investigation of the interleukin (IL)-4/IL-4 receptor system in promyelocytic leukaemia PLB-985 cells during differentiation toward neutrophil-like phenotype: mechanism involved in IL-4-induced SOCS3 protein expression. 1800 66


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