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)

Recent studies have indicated that airway inflammation in atopic asthma is characterized by T-cell activation and local eosinophilia, but it is unknown whether this also applies to nonatopic asthma. In this study, the cytokine mRNA profile and activation status of inflammatory cells in bronchoalveolar lavage fluid (BALF) of eight nonallergic patients with symptomatic asthma and eight nonallergic healthy controls were compared using the message amplification phenotyping (MAPPing) with the polymerase chain reaction (PCR) procedure and immunocytochemical evaluation. Asthmatics had an increasing number of inflammatory cells in BALF, including activated eosinophils (EG2-positive) (p less than 0.001) and activated T cells (CD25-positive) (p less than 0.001). Activated T cells from five of the eight asthmatic patients and from one control subject expressed high levels of interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF). All the asthmatic patients had increased numbers of monocytes in their BALF (p less than 0.002) and those cells invariably showed increased expression of interleukin 1 beta (IL1 beta) transcripts. In five patients they also expressed appreciable levels of IL-6 and GM-CSF mRNA. IL-5 and GM-CSF can induce local activation of eosinophils, and IL-1 beta and IL-6 are known to promote T-cell activation and proliferation. Thus, there is an increased production of cytokines with inflammatory properties in the airways of patients with nonatopic symptomatic asthma, which may contribute to the persistence of inflammation, and monocytes and activated T cells are important sources of these cytokines.
Chest 1992 Sep
PMID:Cytokine mRNA profile and cell activation in bronchoalveolar lavage fluid from nonatopic patients with symptomatic asthma. 151 85

Experiments were undertaken to investigate the molecular basis of primitive hematopoietic progenitor cell regulation in both the long-term culture system and in methylcellulose, particularly with a view to characterizing factors either able or unable to influence the behaviour of primitive leukemic cells from patients with chronic myeloid leukemia (CML). Long-term cultures of CML cells with or without irradiated normal marrow feeder layers were initiated from peripheral blood cells of CML patients with high white blood cell counts. Three weeks later the effect of exogenously added transforming growth factor-beta 1 (TGF-beta 1) on progenitor cycling status was examined. A single addition of 5 ng/ml TGF-beta 1 was able to reversibly arrest the otherwise uninterrupted turnover of primitive leukemic erythroid and granulopoietic progenitors for a period of up to 7 days both in the presence and absence of a normal adherent cell population. When TGF-beta 1 was incorporated into methylcellulose cultures, its ability to inhibit colony formation by CML progenitors showed the same differential activity on primitive cell types exhibited by normal progenitors. Dose-response curves for analogous populations of normal and leukemic cells were indistinguishable. Increasing the concentration of granulocyte-macrophage colony-stimulating factor (GM-CSF) in methylcellulose colony assays decreased the sensitivity displayed by normal clonogenic cells to TGF-beta 1 and no differences were detectable when CML cells were used in such regulator competition experiments. These findings support a general model of primitive hematopoietic cell regulation in which entry into S-phase is determined at the intracellular level by multiple convergent pathways that may deliver either positive or negative signals from activated cell surface receptors for distinct extracellular factors. The present study shows for the first time that primitive CML progenitors exposed to TGF-beta 1 in vitro can be transiently blocked in a noncycling state for several days without loss of viability and that the mechanisms responsible for the emergence and maintenance of a clonal population of CML cells in vivo do not appear to involve changes in their sensitivity to TGF-beta 1. It is thus unlikely that the heightened proliferative activity exhibited by primitive CML progenitors both in vivo and in long-term culture can be explained by an abnormality in the intracellular mechanisms normally activated by TGF-beta 1 receptor-ligand binding. We suggest that primitive CML cells are either defective in their ability to see (or activate) endogenously produced TGF-beta 1, or are defective in their responsiveness to another, undefined, regulator.
Leukemia 1992 Sep
PMID:Granulocyte-macrophage colony-stimulating factor modulation of the inhibitory effect of transforming growth factor-beta on normal and leukemic human hematopoietic progenitor cells. 151 2

We examined the distribution of calpains I and II in human hematopoietic system cell lines by Western and Northern blot analyses and enzyme activity assay. Expression of calpain I, a low Ca(2+)-requiring cysteine protease, was observed in all human T-cell lines tested. By contrast, expression of calpain II, a high Ca(2+)-requiring form, in human T-cells was closely correlated with human T-cell leukemia virus type I (HTLV-I) infection, which is known to result in the expression of adult T-cell leukemia-associated antigens, interleukin-2 (IL-2) receptor alpha, and Ca(2+)-dependent cell proliferation. Specific expression of calpain II in HTLV-I-infected cells occurred at the mRNA level. Furthermore, expression of calpain II in human natural killer-like cells was augmented by HTLV-I pX gene transfection. In HTLV-I-infected cells, the trans-acting transcriptional activation of the long terminal repeat and control elements for the IL-2 receptor alpha, c-fos, and granulocyte-macrophage colony-stimulating factor genes by the Tax from the pX gene is already known. Our results suggest that the similar trans-activation occurs to the calpain II gene in HTLV-I-infected hematopoietic system cells.
J Biol Chem 1992 Sep 25
PMID:Expression of calpain II gene in human hematopoietic system cells infected with human T-cell leukemia virus type I. 152 57

Cell-free synovial fluid from patients with rheumatoid arthritis stimulated the NADPH oxidase activity in human neutrophils, which reached a peak 15-20 min after addition. Insoluble immunoglobulin aggregates isolated from these fluids activated a similar pattern of oxidase activity. However, when synovial fluid was added to neutrophil suspensions which had been previously exposed to granulocyte-macrophage colony-stimulating factor, the stimulated oxidase activity was biphasic, in that an additional transient activity was observed which reached a peak within 5 min of addition. The additional neutrophil-stimulating activity could not be sedimented by centrifugation at 330,000 g-min, and only activated oxidase activity in neutrophils which had previously been primed. The neutrophil-stimulating activity in this soluble fraction was removed by Protein A affinity chromatography, and activity was recovered in eluates from this column. Thus activity in this soluble fraction from synovial fluid is attributed to the presence of soluble immunoglobulin aggregates. Whereas oxidase activity stimulated by the isoluble immunoglobulin aggregates was inhibited by staurosporine (and hence largely dependent on the activity of protein kinase C), the activity stimulated by the soluble immunoglobulin aggregates was staurosporine-insensitive. The soluble immunoglobulin aggregates were present at significantly higher levels in synovial fluids from patients with rheumatoid arthritis compared with those from other joint arthropathies. Thus rheumatoid synovial fluids possess heterogeneous immunoglobulin aggregates which activate neutrophils via distinct molecular pathways. As neutrophils within rheumatoid joints are primed, the soluble immunoglobulin aggregates are likely to be of importance in disease pathology.
Biochem J 1992 Sep 01
PMID:Activation of neutrophil reactive-oxidant production by synovial fluid from patients with inflammatory joint disease. Soluble and insoluble immunoglobulin aggregates activate different pathways in primed and unprimed cells. 153 May 67

Mouse C1 line cells are megakaryoblastic cells established by coinfection of Abelson murine leukemia virus and recombinant simian virus 40. We examined the effects of various compounds on growth and differentiation of these cells. Megakaryocytic differentiation of C1 cells was not induced by cytokines that stimulate megakaryocytic maturation of normal progenitor cells, such as interleukin 3 and 6 and granulocyte-macrophage colony-stimulating factor. However, the cells were induced to differentiate into megakaryocytes by treatment with some protein kinase inhibitors. The inhibition of v-abl tyrosine kinase activity preceded induction of differentiation of the cells treated with tyrosine kinase inhibitors such as genistein, herbimycin A, and erbstatin. Treatment of C1 cells with a v-abl antisense oligomer inhibited their proliferation and induced acetylcholinesterase activity, a typical marker of megakaryocytic differentiation. These results suggest that inhibition of v-abl function is associated with induction of megakaryocytic differentiation of C1 cells. Among the compounds tested, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7), a potent inhibitor of cyclic nucleotide-dependent and Ca(2+)-phospholipid-dependent (protein kinase C) protein kinases, was the most potent inducer of differentiation of C1 cells. However, the differentiation-inducing effect of H-7 was unlikely to be mediated through inhibition of protein kinase C or cyclic nucleotide-dependent kinases, because other types of inhibitors of these kinases were not effective, and a protein kinase activator (phorbol ester) induced differentiation of C1 cells. Moreover, neither v-abl mRNA expression nor v-abl kinase activity in C1 cells was affected by treatment with H-7. These findings indicate that induction of megakaryocytic differentiation by H-7 is not related to inhibition of v-abl kinase, but rather to some novel function of H-7.
Cancer Res 1991 Sep 01
PMID:Induction by some protein kinase inhibitors of differentiation of a mouse megakaryoblastic cell line established by coinfection with Abelson murine leukemia virus and recombinant SV40 retrovirus. 165 10

The mechanisms which control the production of erythropoietin (Epo) remain enigmatic. Recent data suggest that the half-time of Epo messenger RNA (mRNA) is increased by hypoxia in Hep 3B cells, a human hepatoma line. The post-transcriptional regulation of other rapidly degraded mRNAs is mediated by sequence-specific mRNA binding proteins. In order to determine if Epo mRNA specific binding proteins exist, we probed cytosolic lysates from Hep 3B cells and mouse tissues with radiolabeled Epo RNA. A cytosolic protein that binds specifically to Epo RNA was identified in the Epo-producing, hepatoblastoma Hep 3B cell line by gel mobility shift assay. This protein was identified in both normoxic and hypoxic cells and bound specifically to a 120-base fragment of the 3'-untranslated region (3'-UTR) of Epo mRNA. Binding was completed with unlabeled Epo RNA, but not with granulocyte-macrophage colony-stimulating factor RNA. Ultraviolet light cross-linked Epo RNA-protein complexes migrated as two bands of 70 and 135-140 kD on sodium dodecyl sulfate-polyacrylamide gels. Binding activity was markedly increased in brain and spleen lysates from mice subjected to 24 h of hypoxia. Therefore, the post-transcriptional regulation of Epo expression in response to hypoxia may in part be due to the interaction of Epo RNA with its specific binding protein.
J Biol Chem 1991 Sep 05
PMID:Hypoxia up-regulates the activity of a novel erythropoietin mRNA binding protein. 165 42

Preincubation of human neutrophils with the human hormone granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibits the specific binding of leukotriene B4 ([3H]LTB4) but not the nonmetabolizable bioactive platelet-activating factor ([3H]C-PAF) to intact cells. This inhibition requires that the GM-CSF interacts with intact cells. The action of GM-CSF is not prevented by pertussis toxin. Moreover, the rise in calcium produced by LTB4 but not by PAF is also inhibited in human neutrophils pretreated with GM-CSF. Interestingly, neither the inhibitory action of GM-CSF on [3H]LTB4 binding or LTB4-induced calcium rise nor the potentiation of superoxide production by GM-CSF is reduced by inhibitors of arachidonic acid metabolism by the lipoxygenase pathway. In contrast, preincubation of human neutrophils with either the chemotactic factor formyl-methionyl-leucyl-phenylalanine (fMet-Leu-Phe) or the active phorbol ester, phorbol 12-myristate 13-acetate (PMA), inhibits the binding of both [3H]LTB4 and [3H]C-PAF to intact cells. The inhibitory actions of GM-CSF, PMA, and fMet-Leu-Phe require that they interact with the intact cells; their actions cannot be reproduced in plasma membrane preparations. The effects of both GM-CSF and fMet-Leu-Phe cannot be prevented by the protein kinase C inhibitor staurosporine. The mechanisms of fMet-Leu-Phe and GM-CSF actions are probably not mediated through the release of LTB4 by the cells. Interestingly, this new action, unlike other reported effects of GM-CSF, is not mediated through a pertussis toxin-sensitive G protein (Gi alpha 2). This indicates that not all GM-CSF receptors are coupled to Gi alpha 2.
Am J Physiol 1991 Sep
PMID:Modulation of leukotriene B4 and platelet-activating factor binding to neutrophils. 165 24

Most studies of antibody-dependent cellular cytotoxicity (ADCC) by polymorphonuclear leukocytes (PMN) have supported oxidative lytic processes. This may be because the studies used nonhuman or nonneoplastic cells that were highly sensitive to reactive oxygen species or were small enough to be phagocytosed by PMN. We therefore investigated whether oxygen radicals participate in PMN cytotoxicity toward human neuroectodermal solid tumor cells sensitized by 3F8, which is an anti-ganglioside GD2 murine IgG3 monoclonal antibody with documented anticancer activity in humans. A 4-h 51Cr release assay was used to assess tumor cell lysis by hydrogen peroxide, superoxide, and hypochlorite. Nine of 11 GD2(+) human melanoma and neuroblastoma cell lines had equal or greater resistance to these oxidants as compared to a GD2(-) human carcinoma line (SKBr1-III) found by others (and confirmed by us) to be significantly more resistant to oxidative lysis than a murine cell line (P388D1) representative of those commonly used in cytotoxicity assays. To facilitate detection of oxidant-mediated lysis, subsequent studies of 3F8-mediated ADCC used GD2(+) targets that were relatively sensitive and others that were relatively resistant to oxygen radicals. Normal PMN and PMN obtained from children with chronic granulomatous disease, which do not generate reactive oxygen species, were equally effective in ADCC. Granulocyte-macrophage colony-stimulating factor, which primes oxidative responses of normal but not of chronic granulomatous disease PMN, enhanced ADCC by both kinds of PMN. During ADCC of 3F8-sensitized targets, with or without granulocyte-macrophage colony-stimulating factor, GD2(-) "innocent bystander" tumor cells (including P388D1) were not lysed, a finding consistent with unimportant extracellular release of cytotoxic mediators. Finally, antioxidant and antimyeloperoxidase moieties did not block ADCC. We conclude that oxidants are not key factors in 3F8-mediated lysis by PMN of human neuroectodermal tumor cells.
Cancer Res 1991 Sep 15
PMID:Clinically effective monoclonal antibody 3F8 mediates nonoxidative lysis of human neuroectodermal tumor cells by polymorphonuclear leukocytes. 165 2

The capacity of alveolar macrophages and peripheral blood monocytes from patients with non-small cell lung cancer to develop tumoricidal function after in vitro stimulation with different macrophage activators was investigated. Alveolar macrophages were found to be impaired in their ability to develop cytotoxic activity compared with either the peripheral blood monocytes from the same patients or alveolar macrophages from patients with nonmalignant lung disorders. This result was observed consistently under diverse culture conditions and with different macrophage activators including gamma-interferon (gamma-IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), phorbol myristate acetate, or endotoxin. The impairment in tumoricidal function observed in alveolar macrophages was not associated with reduced target cell binding compared to peripheral blood monocytes. Alveolar macrophages from patients with lung cancer were found to secrete significantly greater amounts of tumor necrosis factor (TNF) and interleukin-1 (IL-1) than either peripheral blood monocytes from the same patients or alveolar macrophages from the patients with nonmalignant disorders. These results are consistent with either different regulatory pathways for cytotoxicity and cytokine secretion in the alveolar macrophages of patients with lung cancer or diversity in the subpopulations of cells responsible for these functions.
Cancer 1991 Sep 01
PMID:Impaired tumoricidal function of alveolar macrophages from patients with non-small cell lung cancer. 165 12

Human granulocyte-macrophage colony-stimulating factor (hGM-CSF) secreted by a hepatoma cell line, HA22T/GVH, was purified and assessed for its effects in vivo on blood leukocytes and bone marrow granulocyte-macrophage progenitor cells (CFU-GM) in ICR mice pretreated with a sublethal dose of cyclophosphamide (cytoxan). The hGM-CSF preparations were natural and had no detectable endotoxin. Five days after the administration of 300 mg/kg cytoxan, severe leukopenia with marked myelopoietic suppression was induced. The cytoxan-treated mice were then injected intraperitoneally with 10,000 units of purified hGM-CSF/mouse daily for three days. Leukopenia was totally abrogated and the leukocyte number greatly increased to a level 2- to 3-fold higher than in GM-CSF-uninjected mice. Differential white cell count showed that the subpopulations of leukocytes responsive to hGM-CSF stimulation were mainly of neutrophils and monocytes, while the lymphocytes remained unaffected. Meanwhile, in the bone marrow, hGM-CSF administration induced an apparent (3-fold) increase in the number of myeloid progenitor cells, CFU-GM. However, the effect in vivo of a single hGM-CSF injection could only maintain for 48 hrs. In addition, the loss in body weight caused by cytoxan was less in the mice with subsequent hGM-CSF than those without CSF. These results suggest that injection of GM-CSF can effectively reconstitute the cytotoxic drug-damaged myelopoiesis without apparent in vivo toxic reaction.
Zhonghua Yi Xue Za Zhi (Taipei) 1991 Sep
PMID:In vivo stimulation of myelopoiesis in cyclophosphamide-treated mice by purified human GM-CSF. 165 33


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