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 number of growth factors have been identified that participate in lung growth and repair. The early stages of the repair cascade are important in preventing the later development of fibrosis. Both transforming growth factor-beta and basic fibroblast growth factor can have beneficial effects when given early in some injury models. Keratinocyte growth factor stimulates type II cell hyperplasia in vitro but has not yet been studied in a lung injury model. Excessive production of growth factors such as transforming growth factor-alpha and transforming growth factor-beta can lead to fibrosis. Granulocyte-macrophage colony-stimulating factor is implicated in asthma, but now that knockout mice have been shown to have a histologic picture similar to pulmonary alveolar proteinosis, a new role for this factor in pulmonary disease has been suggested. Increasing our understanding of the diverse actions and interactions of growth factors in the lung will bring us closer to therapeutic interventions that can prevent some chronic lung diseases.
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PMID:Role of growth factors in lung repair and diseases. 766 10

The aims of this study were: to quantify immunoreactive tumour necrosis factor alpha (TNF-alpha) concentrations in maternal plasma and amniotic fluid obtained from women during pregnancy and labour, both at term and preterm; and to establish the effects of bacterial endotoxin and cytokines on the in vitro release of TNF-alpha from intrauterine tissues. Maternal plasma TNF-alpha concentrations did not change during pregnancy (457.2 +/- 102.9 ng/l, mean +/- SEM, N = 52) or at the time of labour (543.5 +/- 138.6 ng/l, N = 43). In contrast, amniotic fluid TNF-alpha concentrations increased significantly (p < 0.05) during pregnancy (early pregnancy, EP, 93.0 +/- 24.8 ng/l, N = 7; preterm not-in-labour, PNIL, 186.8 +/- 42.9 ng/l, N = 16; term not-in-labour. TNIL, 499.7 +/- 150.9 ng/l, N = 13) and in association with preterm labour (preterm in-labour, PIL, 958.7 +/- 575.6 ng/l, N = 5 vs PNIL, 186.8 +/- 42.9 ng/l, N = 16). Choriodecidual and placental explants (N = 3) maintained in in vitro culture released TNF-alpha. Furthermore, the release of TNF-alpha was increased significantly (p < 0.05) by bacterial endotoxin (lipopolysaccharide, 10 ng/l-10 mg/l) but was not affected by the following cytokines at the indicated doses: interleukin-1 alpha (0.28 nmol/l), interleukin-6 (12.5 nmol/l), granulocyte colony-stimulating factor (2.5 nmol/l), granulocyte-macrophage colony-stimulating factor (35 nmol/l), macrophage colony-stimulating factor (1.2 nmol/l), leukaemia inhibitory factor (0.45 nmol/l) and transforming growth factor-beta (0.4 nmol/l).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Tumour necrosis factor alpha during human pregnancy and labour: maternal plasma and amniotic fluid concentrations and release from intrauterine tissues. 780 44

Monocytes from different individuals show variable cytokine production in response to a variety of stimuli. We wished to determine the sets of conditions (cytokine combinations) that would enable us to demonstrate stable inter-individual differences in the production of IL-1 alpha, IL-1 beta, IL-1Ra, on-6 and tumour necrosis factor-alpha (TNF-alpha) by monocytes. We assessed the ability of a number of recombinant human cytokines (granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon-gamma (IFN-gamma), TNF-alpha, IL-4, IL-6, transforming growth factor-beta (TGF-beta), IL-10 and IL-1Ra)) to stimulate or inhibit the production of one or more of these monocyte products. GM-CSF was found to stimulate the production of all five of these cytokines in a highly reproducible manner. TNF-alpha also up-regulated production of IL-1 alpha, IL-1 beta, IL-1Ra and IL-6 by monocytes, but the variability in the results of cells cultured from the same individuals on different occasions was greater. Other cytokines either stimulated production of only some of the five cytokine products tested, or stimulated the production of some cytokine products while inhibiting production of others. This was especially evident when cytokines were used in combination with GM-CSF: IFN-gamma down-regulated production of IL-1Ra while up-regulating the production of IL-1 alpha/beta, IL-6 and TNF-alpha, while IL-4 had the exact opposite effect. Polymorphisms in regions of cytokine genes that affect transcription may account for some of the interindividual variation in cytokine production. We have shown that a stable estimate of cytokine production phenotype can be obtained when monocytes collected on at least two separate occasions are stimulated by GM-CSF in vitro. We have looked for a relationship between IL-1 production and an 86-bp variable repeat polymorphism in intron 2 of the IL-1Ra gene. A less common allele of this polymorphism (allele 2) was associated with increased production of IL-1Ra protein, and also reduced production of IL-1 alpha protein by monocytes.
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PMID:Cytokine production by normal human monocytes: inter-subject variation and relationship to an IL-1 receptor antagonist (IL-1Ra) gene polymorphism. 785 Oct 26

The pentraxins C-reactive protein (CRP) and serum amyloid P component (SAP) are acute-phase proteins produced by liver epithelial cells. PTX3 was recently cloned as an interleukin-1 (IL-1)-inducible gene in endothelial cells, with structural similarities to pentraxins in the C-terminal half of the molecule. The present study was designed to investigate the expression of PTX3 in the human leukocyte populations. Human peripheral blood mononuclear cells exposed to lipopolysaccharide (LPS) or IL-1 beta expressed significant levels of PTX3 mRNA. Tumor necrosis factor-alpha (TNF-alpha) was a less-effective inducer of PTX3, whereas IL-6, monocyte chemotactic protein-1, macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and interferon-gamma were inactive. Among leukocytes, only monocytes exposed to inflammatory cytokines or LPS expressed the PTX3 transcript, which was undetectable in resting or stimulated polymorphonuclear cells, T or B lymphocytes, and natural killer cells. PTX3 mRNA was also inducible in in vitro monocyte-derived macrophages, in tumor-associated macrophages, and in the myelomonocytic cell lines HL60, U937, and THP1, but not in GFD8, with the latter possibly representative of earlier stages of myelomonocytic differentiation. T- and B-cell lines had no detectable PTX3. Inhibition of transcription by actinomycin D blocked induction of PTX3 in monocytes and nuclear run-on analysis showed that LPS induces the expression of the PTX3 gene at the transcriptional level in isolated monocytes. Cycloheximide had no effect on PTX3 induction in U937 cells, but was inhibitory on monocytes exposed to LPS or IL-1 beta. Monoclonal antibody against TNF and the IL-1 receptor antagonists did not inhibit induction of PTX3 in monocytes by LPS, thus excluding these cytokines as secondary stimulators of PTX3. IL-4, but not dexamethasone or transforming growth factor-beta, inhibited PTX3 expression in monocytes. Using a PTX3-specific antiserum, release of PTX3 protein was demonstrated for the first time in stimulated monocytes as well as in endothelial and fibroblastic cells. Thus, PTX3, unlike the classical pentraxins CRP and SAP, is expressed and released by cells of the monocyte-macrophage lineage exposed to inflammatory signals.
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PMID:Inducible expression of PTX3, a new member of the pentraxin family, in human mononuclear phagocytes. 794 2

Bloodstream neutrophils do not express mRNA for interleukin-1 beta (IL-1 beta), but transcripts for this cytokine are rapidly induced following exposure to recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) in vitro. Levels of IL-1 beta mRNA reach maximal values 1 h after exposure to rGM-CSF and then decline to near basal levels by 4 h. Similarly, rGM-CSF treatment of blood neutrophils in vitro induced increases in levels of mRNA for IL-6 and tumour necrosis factor-alpha (TNF-alpha). RNA extracted from neutrophils isolated from the synovial fluid of patients with rheumatoid arthritis expressed low, but significant levels of IL-1 beta mRNA that were between 0.5 and 3% of the levels that could be maximally induced by rGM-CSF treatment of blood neutrophils. However, transcripts for TNF-alpha and IL-6 were not detected in these synovial fluid neutrophils. mRNA for transforming growth factor-beta (TGF-beta) was constitutively expressed in blood and synovial fluid neutrophils and transcripts for this cytokine were not altered by rGM-CSF exposure. Because of the transient nature of IL-1 beta expression by activated neutrophils, we propose that the low levels of expression of mRNA for this cytokine in the synovial fluid neutrophils represents expression by a small, perhaps newly-recruited and activated, sub-population of cells. IL-1 beta expression by this sub-population may thus contribute to the pathogenesis of rheumatoid disease.
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PMID:Cytokine expression by inflammatory neutrophils. 800 60

Metabolism of dehydroepiandrosterone sulfate (DHEAS) to dehydroepiandrosterone (DHEA) occurs within specific anatomical compartments in vivo through the actions of the enzyme DHEAS sulfatase. This enzymatic activity facilitates the conversion of hydrophilic DHEAS to the hydrophobic species DHEA, which can then be further metabolized to other steroid hormones. High levels of DHEAS sulfatase reside in tissues where the biological activity of DHEA or its downstream metabolites regulate cellular function. Therefore, control over the activity of DHEAS sulfatase may represent an important regulatory process for the production of DHEA and its metabolites. Homogeneous populations of macrophages from normal mice were found to effectively convert DHEAS to DHEA in vitro. DHEAS sulfatase activity could be markedly depressed after exposure of these cells to a variety of nonspecific macrophage activators [i.e. zymosan, polyinosine/cytosine, heat-killed bacteria, or bacterial lipopolysaccharide (LPS)]. Inhibition of DHEAS metabolism was found to require protein synthesis, because temporary abrogation of protein synthesis with cycloheximide eliminated the ability of LPS to depress the conversion of DHEAS to DHEA. Additionally, exposure of LPS-nonresponsive macrophages to supernatants derived from LPS-treated BALB/c macrophages inhibited their ability to convert DHEAS to DHEA. Potent inhibition of sulfatase activity could be achieved by directly exposing murine macrophages to interferon-alpha (IFN alpha), IFN beta, or tumor necrosis factor-alpha, but not interleukin-1, interleukin-6, granulocyte-macrophage colony-stimulating factor, transforming growth factor-beta, platelet-derived growth factor, or the T-cell product IFN gamma. Our results indicate that macrophage metabolism of DHEAS to DHEA is down-regulated after cellular activation. Furthermore, inhibition of DHEAS sulfatase activity appears to be mediated through the actions of the inflammatory cytokines tumor necrosis factor-alpha and IFN alpha/beta.
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PMID:Regulation of macrophage dehydroepiandrosterone sulfate metabolism by inflammatory cytokines. 801 93

The mechanism of growth inhibition mediated by tumor necrosis factor (TNF) is unclear. Since recent data strongly suggested that generation of superoxide is a key step in cytotoxicity of TNF, we reasoned that cells expressing high levels of enzymes that degrade superoxide radicals would be resistant to TNF. Therefore, we examined the TNF-sensitivity of bone marrow progenitor cells of transgenic mice that expressed the gene for human copper zinc-superoxide dismutase (CuZn-SOD). The CuZn-SOD is a key enzyme in the metabolism of superoxide radicals. Heterozygous and homozygous transgenic mice had 3- and 5-fold increased levels of CuZn-SOD activity, respectively. Bone marrow cells of transgenic and nontransgenic mice were plated in soft gel culture with TNF (0.01-100 ng/ml). TNF inhibited myeloid colony formation supported by either granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF from nontransgenic mice in a dose-dependent manner. In contrast, the myeloid clonal growth of homozygote transgenic mice was not inhibited by TNF at concentrations up to 100 ng/ml. As expected, the effects of TNF on erythroid clonogenic cells, which do not produce superoxide, and the action of transforming growth factor-beta on myeloid progenitor cells, were similar in both transgenic and nontransgenic mice. These results suggest that the mechanism of TNF-mediated growth inhibition of hematopoietic cells occurs through production of superoxide.
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PMID:Hematopoietic progenitor cells of transgenic mice with increased copper/zinc-superoxide dismutase activity are resistant to tumor necrosis factor. 804 Jan 83

Previous studies in our laboratory demonstrated an altered immuno-endocrine feedback communication via the hypothalamo-pituitary-adrenal (HPA) axis, which may be an important modulatory factor in the development of spontaneous autoimmune thyroiditis in Obese strain (OS) chickens. These birds show a significantly lower, or even absent, increase in serum glucocorticoid levels in response to an intravenous injection of antigen or conditioned medium (CM) from mitogen-stimulated spleen cells known to contain glucocorticoid-increasing factors (GIFs), notably interleukin-1 (IL-1). The present study was aimed at investigating this feedback regulation in animal models with spontaneous systemic autoimmune diseases, such as the UCD-200 chicken, which serves as a model for human scleroderma, and various murine lupus models. In contrast to OS chickens, UCD-200 chickens displayed a nearly normal plasma corticosterone surge in response to CM, and IL-1 was again identified as the primary GIF in CM. Recombinant IL-1 also induced a drastic increase in plasma corticosterone levels in various strains of normal mice. A similar increase was observed in the bacterial lipopolysaccharide-resistant C3H/HeJ strain, thus excluding the possibility of bacterial endotoxin contamination. However, in young lupus-prone (NZB/W)F1 and MRL/MP-lpr mice, a significantly lower increase in plasma corticosterone levels was observed after injection of recombinant IL-1, suggesting a deficient immuno-endocrine communication via the HPA loop in this instance as well. Detailed studies to identify further cytokines with GIF activity in the avian and murine systems showed that both IL-6 and tumor necrosis factor-alpha could induce increased plasma corticosterone levels in mice, but not in chickens. IL-3, IL-8, transforming growth factor-beta, interferon-gamma and granulocyte-macrophage colony-stimulating factor were devoid of GIF activity in both chickens and mice.
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PMID:Disturbed immuno-endocrine communication via the hypothalamo-pituitary-adrenal axis in autoimmune disease. 821 76

Cutaneous I-A+ Langerhans cells are the principal antigen-presenting cells within the epidermis, capable of both initiating and eliciting CD4-dependent immune reactions. We recently demonstrated that epidermal Langerhans cells can present tumor-associated antigens and thus may be important in cutaneous tumor immunity. Despite the ability of Langerhans cells to present tumor antigens, they generally fail to induce protective tumor immunity against growing tumors in situ. We therefore investigated whether locally produced cytokines may be able to down-regulate the presentation of tumor-associated antigens and alloantigen by epidermal antigen-presenting cells in primed as well as in unprimed systems in vivo and in vitro. Naive syngeneic mice could be successfully immunized against the spindle cell tumor S1509a by injecting them with granulocyte-macrophage colony-stimulating factor-exposed and tumor-associated antigen-pulsed epidermal cells three times at weekly intervals. Co-incubation of epidermal cells in granulocyte-macrophage colony-stimulating factor and interleukin-1 alpha inhibited tumor-antigen presentation by epidermal antigen-presenting cells in this system and also inhibited alloantigen presentation in the primary mixed epidermal cell-lymphocyte reaction. Tumor necrosis factor-alpha appeared to be a significant mediator of the inhibitory effect of interleukin-1 alpha on the ability of epidermal antigen-presenting cells to induce protective tumor immunity, because addition of anti-tumor necrosis factor-alpha antibody abrogated the observed effect of interleukin-1 alpha. However, the effects of interleukin-1 alpha and tumor necrosis factor-alpha differed with regard to presentation of tumor-associated antigens by epidermal antigen-presenting cells in a primed system. Whereas incubation of epidermal cells in interleukin-1 alpha before or after tumor antigen pulse inhibited their ability to elicit a delayed-type hypersensitivity response against S1509a tumor-associated antigens in tumor-immune mice, culture in tumor necrosis factor-alpha significantly enhanced delayed-type hypersensitivity. Again, these in vivo data corresponded well to similar results obtained in vitro using the secondary mixed epidermal cell-lymphocyte reaction. Incubation of epidermal cells in transforming growth factor-beta, which has been shown to down-regulate T-cell-mediated immune responses in other systems, did not suppress tumor immunity in our assays. Thus, interleukin-1 alpha may be an important regulator of Langerhans cell antigen-presenting function, having effects that are partially mediated via interleukin-1 alpha-induced up-regulation of tumor necrosis factor-alpha secretion within the skin.
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PMID:Interleukin 1 alpha but not transforming growth factor beta inhibits tumor antigen presentation by epidermal antigen-presenting cells. 828 13

Murine intraepithelial lymphocytes (IEL) respond poorly to T cell mitogens and to monoclonal antibody stimulation of T cell receptor (TCR)- and CD3- associated molecules. In contrast, we found that a soluble extract of Mycobacterium tuberculosis (Mtb), but not purified protein derivative of tuberculin, induced significant proliferative responses in IEL cultures. The active component was apparently a heat shock protein (HSP), since recombinant 71-kDa HSP from Mtb induced IEL to proliferate, while 65-kDa HSP from M. bovis and M. leprae did not. Both alpha/beta and gamma/delta TCR-enriched IEL gave proliferative responses to 71-kDa HSP. Further, culture supernatants from IEL stimulated with 71-kDa HSP contained elevated levels of interleukin-(IL)-3/granulocyte-macrophage colony-stimulating factor, interferon-gamma and IL-6, but not IL-2, IL-4, IL-5 or transforming growth factor-beta. Finally, several IEL T cell clones have been maintained for up to 6 weeks, when stimulated with 71-kDa HSP, IL-2 and feeder cells. Our results show that the 71-kDa HSP of Mtb induces IEL T cells to divide and to secrete cytokines and this may offer a model for cloning and study of IEL T cells in vitro.
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PMID:The Mycobacterium tuberculosis 71-kDa heat-shock protein induces proliferation and cytokine secretion by murine gut intraepithelial lymphocytes. 834 73


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