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)

Nitric oxide is a short-lived reactive mediator that inhibits bone marrow (BM) cell proliferation induced by granulocyte-macrophage colony-stimulating factor (GM-CSF). The present studies show that nitric oxide also inhibits macrophage colony-stimulating factor (M-CSF)-induced growth of mouse BM cells, an effect that was dependent on the presence of an inflammatory mediator and blocked by the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMA). Treatment of mice with the hematotoxicant benzene (800 mg/kg, intraperitoneally, two times per day, for 2 days) resulted in a significant increase in nitric oxide production by BM cells stimulated with lipopolysaccharide (LPS) and interferon gamma alone or in combination with M-CSF or GM-CSF. Cells from benzene-treated mice also displayed increased sensitivity to the growth-promoting effects of M-CSF and GM-CSF. These results suggest that benzene treatment of mice primes BM cells to inducers of nitric oxide. Northern blot analysis showed that this was, at least in part, caused by increased expression of mRNA for inducible nitric oxide synthase (iNOS). Surprisingly, treatment of mice with L-NMA was found to cause a depression in BM cell proliferation and to potentiate benzene-induced decreases in BM cellularity and increases in nitric oxide production. L-NMA administration also augmented nitric oxide production by BM cells. These data indicate that L-NMA is hematotoxic and suggest that it may have actions distinct from inhibition of nitric oxide synthase in the BM.
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PMID:Enhanced production of nitric oxide by bone marrow cells and increased sensitivity to macrophage colony-stimulating factor (CSF) and granulocyte-macrophage CSF after benzene treatment of mice. 819 60

MHC class II+ lung dendritic cells (DC) increase in number following treatment of animals with interferon-gamma (IFN-gamma) [Kradin et al. (1991) Am. J. Resp. Mol. Biol. 4, 210; Gong et al. (1992)J. Exp. Med. 175, 797]. To test whether this is due to increased sequestration and/or trafficking of DC to the lung, bone marrow DC from BALB/c mice were obtained by culturing bone marrow with granulocyte-macrophage colony-stimulating factor (GM-CSF). Recipient BALB/c mice were injected intraperitoneally (i.p.) for 4 days with one of the following: IFN-gamma, dexamethasone (Dex), or phosphate-buffered saline (PBS). Twenty-four hours after the last dose, they were injected intravenously (i.v.) with carboxyfluorescein (F1) -labeled DC (1 x 10(6)/mouse) and killed 4 h later. DC, double immunostained for Ia and F1, were quantified by morphometry in frozen sections of lung. The number of injected dual-labeled DC/cm2 was reduced by 90% in IFN-gamma-treated mice. By contrast, there was no significant difference between Dex- and PBS-treated animals in the number of double-labeled DC retained in pulmonary capillaries. Biodistribution and imaging studies were conducted on IFN-gamma- and PBS-treated mice using 111In-labeled DC. Reduced radioactivity in the lung was accounted for by an equivalent increase in the liver of IFN-gamma-treated mice; imaging studies confirmed these observations. Removal of >80% of alveolar macrophages (AM) by pretreatment with intratracheally administered chlodronate-loaded liposomes did not change the biodistribution of DC in IFN-gamma- and PBS-injected mice. Serum levels of tumor necrosis factor-alpha (TNF-alpha and nitrite/nitrate in IFN-gamma-treated mice were similar to those of controls. Immunostaining for inducible nitric oxide synthase (iNOS), however, revealed a 1.5-and 6-fold increase in the number of positively stained cells in the lung and liver, respectively, of IFN-gamma-treated mice; the number of iNOS-expressing cells was markedly reduced in Dex-treated animals relative to controls. To test whether the systemic treatment with IFN-gamma stimulated the cytotoxic activity of Kupffer cells, mice were injected with chlodronate liposomes 5 days before death. After treating the mice in the ensuing 4 days with IFN-gamma or PBS, biodistribution and imaging studies with 111In-labeled DC were conducted on the 5th day. After administration of chlodronate liposomes, there was a significant increase in the radioactivity detected in the lungs of IFN-gamma-injected mice but not in those of PBS- injected controls, a finding confirmed by imaging studies. We conclude that IFN-gamma treatment augmented Kupffer cell cytotoxic activity, which, in turn, effectively reduced the number of injected DC in circulation, with the result that fewer of these cells were retained in the lung vasculature. We further conclude that IFN-gamma increases the number of Ia+ lung DC by up-regulating Ia expression of resident Ia- DC precursors and not by promoting the migration of circulating DC to the lung.
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PMID:Interferon-gamma reduces Ia+ dendritic cell traffic to the lung. 886 37

The role of Rel in the monocyte/macrophage lineage was examined in mice with an inactivated c-rel gene. Although the frequency of monocytic cells was normal in Rel-/- mice, we show that Rel serves distinct roles in regulating gene expression and immune effector function in different mature macrophage populations. Stimulated Rel-/- resident peritoneal macrophages produced higher than normal levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6), but tumour necrosis factor-alpha (TNF-alpha) production was not induced. Diminished cytotoxic activity exhibited by resident Rel-/- macrophages was consistent with reduced nitric oxide production resulting from impaired up-regulation of inducible nitric oxide synthase expression. While a similar altered pattern of IL-6 and TNF-alpha expression was observed in stimulated Rel-/- peritoneal effusion macrophages, cytotoxic activity, nitric oxide, GM-CSF and G-CSF production by these cells was normal. The alternate regulation of certain genes in the two macrophage populations coincided with different patterns of nuclear Rel/NF-kappaB complexes expressed in normal resident and elicited cells. Collectively, these results establish that Rel is a positive or negative regulator of transcription in macrophages and that Rel has distinct roles in different macrophage populations.
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PMID:The Rel subunit of NF-kappaB-like transcription factors is a positive and negative regulator of macrophage gene expression: distinct roles for Rel in different macrophage populations. 900 85

The influence of the anti-allergy agent azelastine hydrochloride (Azeptin) on NF-kappa B activation associated with the generation of cytokines and nitric oxide (NO) was investigated in various kinds of human and mouse cells. Azeptin dose-dependently suppressed both DNA and protein synthesis in human gingival fibroblasts (HF) and also suppressed blastogenesis of human peripheral blood lymphocytes (PBL). Generation of tumor necrosis factor-alpha, interleukin 1-beta, granulocyte-macrophage colony-stimulating factor and interleukin-6 from 10(-5) M Azeptin-treated PBL and human monocytes (HM) was decreased to approximately 1/3 to 2/3 of the control levels. In parallel with the decreased cytokine generation, each cytokine mRNA was less expressed in the presence of 10(-5) M Azeptin. In addition, both inducible nitric oxide synthase-mRNA level and NO generation in mouse peritoneal macrophages were suppressed by 10(-5) M Azeptin. Being compatible with those results, Azeptin (10(-5) M) suppressed activation of NF-kappa B in PBL, HM and HF. These results appear to indicate that suppression of cytokine and NO generation by Azeptin results at least partially from the inhibition of NF-kappa B activation.
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PMID:Suppression by azelastine hydrochloride of NF-kappa B activation involved in generation of cytokines and nitric oxide. 907 48

Previously we described that the adoptive transfer of tumor-infiltrating lymphocytes (TIL) + interleukin-2 (IL-2) leads to eradication of established methylcholanthrene (MCA)-105 fibrosarcoma pulmonary metastases in a congenic murine model. The in vivo efficacy of TIL was associated with their ability to secrete interferon-gamma (IFN-gamma), and to a lesser extent granulocyte-macrophage colony-stimulating factor. The local secretion of these cytokines resulted in recruitment of naive host immune cells to the tumor and eventually in a successful host antitumor immune response. In the present study, to further evaluate the role of IFN-gamma in the induction of a host antitumor immune response, we compared the treatment efficacy of adoptively transferred T cells and IFN-gamma gene transfected tumor cells (MCA-105/IFN-gamma) as delivery systems of IFN-gamma. Treatment with TIL-IL-2 or irradiated MCA-105/IFN-gamma induced a similar reduction in pulmonary metastases of MCA-105 tumor. In contrast, irradiated wild-type MCA-105 or TIL from IFN-gamma gene knockout mice did not cause tumor eradication. MCA-105 tumor-bearing mice treated with MCA-205/IFN-gamma showed a partial reduction in the number of pulmonary metastases. Histologically, lungs of successfully treated mice showed that initially activated macrophages expressing inducible nitric oxide synthase (iNOS) and dendritic cells infiltrated the tumor bed. Subsequently, CD4+ and CD8+ T cells infiltrated tumors. The therapeutic efficacy of IFN-gamma transfected tumor cells was eliminated when either CD4+ T cells or CD8+ T cells were depleted. These results suggest that local secretion of IFN-gamma induces a tumor-specific host antitumor immune response mediated through activated macrophages, dendritic cells, and tumor-specific T cells. This may be a common component of successful immunotherapy.
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PMID:Local secretion of IFN-gamma induces an antitumor response: comparison between T cells plus IL-2 and IFN-gamma transfected tumor cells. 1040 33

Exposing bovine dendritic cells (DC) and macrophages (MPhi) to Salmonella typhimurium at a ratio of 1 cell to 10 bacteria had a cytotoxic effect that was not evident with a ratio of 1000 cells to 1 bacterium. This lower dose was considered to mimic more closely the in vivo situation and a comparison was made with this model of the consequences of infection for MPhi and DC. DC infected with S. typhimurium up-regulated cell surface expression of major histocompatibility class I (MHC-I), MHC-II, CD40, CD80 and CD86. In contrast, infected MPhi did not exhibit detectable changes in expression of cell surface molecules, except for a marginal increase in CD40. mRNA transcription for tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase was up-regulated in both infected DC and infected MPhi, although mRNA transcription for granulocyte-macrophage colony-stimulating factor and IL-12p40 was up-regulated only in infected DC and for IL-10 was only in infected MPhi. Infected DC had an increased ability to stimulate both allogeneic and antigen-specific T-cell responses compared to non-infected controls. In contrast, infected MPhi showed an increased ability to induce allogeneic responses but this was less than seen for DC and no enhancement of ability to induce antigen-specific T cell responses was seen. Thus, in a low-dose infection model that does not result in the cytotoxicity of a substantial percentage of antigen presenting cells, bovine MPhi and DC respond differently to infection with S. typhimurium and this could have important implications for the development of the immune response.
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PMID:Differential response of bovine monocyte-derived macrophages and dendritic cells to infection with Salmonella typhimurium in a low-dose model in vitro. 1251 3

Resveratrol (3,4',5-trihydroxystilbene) is a polyphenolic stilbene found in the skins of red fruits, including grapes, that may be responsible for some of the health benefits ascribed to consumption of red wine. Resveratrol has been shown to have antioxidant properties and can act as an estrogen agonist. This study examined the anti-inflammatory effects of resveratrol on human airway epithelial cells. Resveratrol and the related molecule quercetin, but not deoxyrhapontin, inhibited IL-8 and granulocyte-macrophage colony-stimulating factor release from A549 cells. Neither the estrogen receptor antagonist tamoxifen nor the glucocorticoid antagonist mifepristone altered the inhibitory effect of resveratrol. The mechanism of resveratrol action was investigated further using luciferase reporter genes stably transfected into A549 cells. Resveratrol and quercetin inhibited NF-kappaB-, activator protein-1-, and cAMP response element binding protein-dependent transcription to a greater extent than the glucocorticosteroid dexamethasone. These compounds also had no significant effect on acetylation or deacetylation of core histones. Resveratrol, but not estradiol or N-acetyl cysteine, inhibited cytokine-stimulated inducible nitric oxide synthase expression and nitrite production (IC50 = 3.6 +/- 2.9 microM) in human primary airway epithelial cells. Resveratrol also inhibited granulocyte-macrophage colony-stimulating factor release (IC50 = 0.44 +/- 0.17 microM), IL-8 release (IC50 = 4.7 +/- 3.3 microM), and cyclooxygenase-2 expression in these cells. This study demonstrates that resveratrol and quercetin have novel nonsteroidal anti-inflammatory activity that may have applications for the treatment of inflammatory diseases.
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PMID:Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. 1518 Sep 20

Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1+/CD11b+ myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, l-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GM-CSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines.
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PMID:High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells. 1534 23

Expression of prostasin in the PC-3 human prostate carcinoma cells inhibited in vitro invasion, but the molecular mechanisms are unknown. Wild-type human prostasin or a serine active-site mutant prostasin was expressed in the PC-3 cells. Molecular changes were measured at the mRNA and the protein levels. Cell signaling changes were evaluated by measuring phosphorylation of the extracellular signal-regulated kinases (Erk1/2) following epidermal growth factor (EGF) treatment of the cells. Protein expression of the EGF receptor (EGFR) was differentially down-regulated by the wild-type and the active-site mutant prostasin. The mRNA expression of EGFR and the transcription repressor SLUG was reduced in cells expressing wild-type prostasin but not the active-site mutant. Phosphorylation of Erk1/2 in response to EGF was greatly reduced by the wild-type prostasin but not by the active-site mutant. The mRNA expression of the urokinase-type plasminogen activator (uPA), the uPA receptor (uPAR), cyclooxygenase-2 (COX-2), and the inducible nitric oxide synthase (iNOS) was decreased by the wild-type and the active-site mutant prostasin. The mRNA or protein expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), matriptase, and E-cadherin was greatly increased by the active-site mutant prostasin. In conclusion, prostasin expression elicits both protease-dependent and independent molecular changes in the PC-3 cells.
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PMID:Prostasin induces protease-dependent and independent molecular changes in the human prostate carcinoma cell line PC-3. 1753 63

Macrophage colony stimulating factor (M-CSF) is a cytokine which has been recently reported to have a neuroprotective effect on ischemic rat brain. In this study, we investigated the effect of chotosan, an oriental medicine, which has been clinically demonstrated to be effective for the treatment of vascular dementia, on M-CSF gene expression in rats with permanent occlusion of bilateral common carotid arteries (P2VO) in vivo and in a C6Bu-1 glioma cell line in vitro. The expression level of M-CSF mRNA in the cerebral cortices of P2VO rats was significantly higher than that in the cerebral cortices of sham-operated animals. Repeated treatment of P2VO rats with chotosan (75 mg/kg per day) for 4 d after P2VO significantly increased the expression level of M-CSF mRNA in the cortex but it had no effect on the expression of beta-actin, granulocyte colony stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF) mRNAs. Moreover, the present in vitro studies revealed that chotosan treatment (10-100 mug/ml) of C6Bu-1 glioma cells dose-dependently enhanced M-CSF mRNA expression without affecting the expression of G-CSF, GM-CSF, and inducible nitric oxide synthase mRNAs. The effect of chotosan was reversed by Ro 31-8220 (1 muM), a selective protein kinase C (PKC) inhibitor, but not by H-89 (10 muM), a selective protein kinase A (PKA) inhibitor. These findings suggest that the upregulatory effect of chotosan on M-CSF mRNA expression involves PKC and may play an important role in the anti-vascular dementia action of this formula.
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PMID:Chotosan enhances macrophage colony-stimulating factor mRNA expression in the ischemic rat brain and C6Bu-1 glioma cells. 1805 7


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