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1.
Cyclosporin (CsA)4, a fungal peptide used clinically for its immunosuppressive properties, was investigated for its ability to antagonize the activation of macrophages (PEM) to the tumoricidal state. The acquisition of tumoricidal properties by PEM challenged with macrophage activating factor (MAF) plus lipopolysaccharide (LPS) was inhibited in a dose-dependent fashion by CsA. Similarly, CsA antagonized activation of PEM exposed to the calcium ionophore, A23187. CsA also inhibited macrophage-mediated tumor cell cytolysis in a dose-dependent manner. These data indicate that in vitro, CsA can modulate directly the acquisition and expression of tumoricidal properties by PEM and suggests that the macrophage may be an important target cell for CsA in vivo. 相似文献
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Inhibition of macrophage activation by calcium channel blockers and calmodulin antagonists 总被引:4,自引:0,他引:4
The biochemical mechanisms by which macrophages become activated to the tumoricidal state are poorly understood. To investigate the role of calcium in this process, the effect of calcium channel blockers and calmodulin antagonists on the acquisition of tumoricidal properties by macrophages activated by a number of different agents was examined. Activation of thioglycollate-stimulated C57BL/6 mouse peritoneal macrophages by macrophage activation factor (MAF) plus LPS, IFN-gamma plus LPS or the calcium ionophore, A23187, was inhibited in a dose-dependent fashion by the calcium channel blockers nifedipine and verapamil. These agents blocked the influx of 45Ca into macrophages activated by MAF plus LPS. Macrophage activation was also inhibited by chlorpromazine, W-7, and calmidazolium at concentrations known to perturb calmodulin function. The data suggest that activation of macrophages to the tumoricidal state is a calcium-dependent process involving the participation of calcium-regulated biochemical reactions whose activities can be modulated by pharmacological agents that frustrate transmembrane calcium fluxes and/or inhibit calmodulin function. 相似文献
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Inhibition of heparin-induced tau filament formation by phenothiazines, polyphenols, and porphyrins 总被引:1,自引:0,他引:1
Taniguchi S Suzuki N Masuda M Hisanaga S Iwatsubo T Goedert M Hasegawa M 《The Journal of biological chemistry》2005,280(9):7614-7623
Tau protein is the major component of the intraneuronal filamentous inclusions that constitute defining neuropathological characteristics of Alzheimer's disease and other tauopathies. The discovery of tau gene mutations in familial forms of frontotemporal dementia has established that dysfunction of the tau protein is sufficient to cause neurodegeneration and dementia. Here we have tested 42 compounds belonging to nine different chemical classes for their ability to inhibit heparin-induced assembly of tau into filaments in vitro. Several phenothiazines (methylene blue, azure A, azure B, and quinacrine mustard), polyphenols (myricetin, epicatechin 5-gallate, gossypetin, and 2,3,4,2',4'-pentahydroxybenzophenone), and the porphyrin ferric dehydroporphyrin IX inhibited tau filament formation with IC(50) values in the low micromolar range as assessed by thioflavin S fluorescence, electron microscopy, and Sarkosyl insolubility. Disassembly of tau filaments was observed in the presence of the porphyrin phthalocyanine. Compounds that inhibited tau filament assembly were also found to inhibit the formation of Abeta fibrils. Biochemical analysis revealed the formation of soluble oligomeric tau in the presence of the inhibitory compounds, suggesting that this may be the mechanism by which tau filament formation is inhibited. The compounds investigated did not affect the ability of tau to interact with microtubules. Identification of small molecule inhibitors of heparin-induced assembly of tau will form a starting point for the development of mechanism-based therapies for the tauopathies. 相似文献
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Antiflammin-1 (AF-1) is a synthetic nonapeptide with a similar sequence to the conserved sequence of CC10 secreted by lung Clara cells. Studies suggest that it is potent inhibitor of inflammation. We investigated the effects and possible mechanisms of AF-1 on LPS-induced alveolar macrophage (AM) activation in vitro. AMs harvested from the BALF of Sprague-Dawley (SD) rat were treated with various concentrations of AF-1 both simultaneously and after LPS stimulation. The concentrations of the cytokines IL-1beta, IL-6, and IL-10 in the supernatant were detected by an enzyme-linked immunosorbent assay. The mRNA expression levels of these cytokines in AMs were analyzed using quantitative RT-PCR. To investigate more fully the possible mechanisms by which AF-1 modulates the expression of cytokines, cells were pretreated with anti-IL-10 antibody. Toll-like receptor-4 (TLR-4) expression on the cell surface was also detected using flow cytometry. The results showed that AF-1 suppressed mRNA expression and protein production of IL-1beta and IL-6, while it promoted IL-10 expression in LPS-stimulated AMs, in a dose-dependent manner. The inhibitory effects of AF-1 on IL-1beta were significantly decreased when endogenous production of IL-10 was blocked. AF-1 also showed an effect on downregulated TLR-4 expression in LPS-stimulated AMs. The data show for the first time that AF-1 modulates the AM response to LPS by regulating TLR-4 expression and upregulating IL-10 secretion, which could be another important mechanism in the AF-1 inhibiting effect on inflammation. 相似文献
5.
Trifluoperazine inhibits superoxide production and O2 uptake by guinea pig neutrophils incubated with arachidonic acid, N-formylmethionylphenylalanine, digitonin or ionophore A23187, with IC50 values of 7–37uM. Since this inhibition is produced by concentrations of trifluoperazine which inhibit interaction of calmodulin with proteins, we examined the effects of two other phenothiazines which interact less effectively with calmodulin. Chlorpromazine, promethazine and trifluoperazine all inhibit N-formylmethionylphenylalanine-stimulated superoxide production with similar efficiency. Furthermore, degranulation stimulated by A23187 or N-formylmethionylphenylalanine is inhibited similarly by all three phenothiazines with IC50 values of 18–45 uM. These results are consistent with the suggestion that phenothiazines may inhibit neutrophil function as a result of non-specific interactions with the cells' membranes rather than by specific interaction with calmodulin. 相似文献
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Inhibition of human erythrocyte Ca++-transport ATPase by phenothiazines and butyrophenones 总被引:4,自引:0,他引:4
Indirect immunofluorescent staining revealed that Prostatic Binding Protein, the major androgen-dependent protein in rat ventral prostate , is associated specifically with the epithelial cells in primary cell cultures derived from rat ventral prostate. The epithelial cells release Prostatic Binding Protein into the medium during primary culture. synthesis of Prostatic Binding Protein is demonstrable during early phases of cell culture. Prostatic Binding Protein is an excellent marker for the identification of functional prostate epithelial cells and for the study of regulation at the cellular level of the synthesis and secretion of a major androgen-dependent prostate protein. 相似文献
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The effect of prostaglandtn E(2), iloprost and cAMP on both nitric oxide and tumour necrosis factor-alpha release in J774 macrophages has been studied. Both prostaglandin E(2) and iloprost inhibited, in a concentration-dependent fashion, the lipopolysaccharide-induced generation of nitric oxide and tumour necrosis factor-alpha. The inhibitory effect of these prostanoids seems to be mediated by an increase of the second messenger cAMP since it was mimicked by dibutyryl cAMP and potentiated by the selective type IV phosphodiesterase inhibitor RO-20-1724. Our results suggest that the inhibition of nitric oxide release by prostaglandin E(2) and iloprost in lipopolysaccharide-activated J774 macrophages may be secondary to the inhibition of tumour necrosis factor-alpha generation, which in turn is likely to be mediated by cAMP. 相似文献
9.
Inhibition of macrophage tumoricidal activity by glucocorticoids 总被引:5,自引:0,他引:5
In this study, the effect of corticosteroids on the activation of macrophages to a fully tumoricidal state was examined. Thioglycolate-elicited peritoneal exudate macrophages from C3H/HeJ mice were rendered cytolytic for P815 mastocytoma cells in a two-signal tumoricidal assay that used recombinant interferon-gamma (rIFN-gamma; 1 to 10 U/ml) as a "priming" signal and butanol-extracted lipopolysaccharide (But-LPS; 0.1 to 5 micrograms/ml) as a "trigger" signal. Treatment of macrophages with either rIFN-gamma alone or But-LPS alone failed to result in significant cytolytic ability. Tumoricidal activity was markedly inhibited in a dose-dependent fashion when glucocorticoids were added simultaneously to the cultures with rIFN-gamma and But-LPS at concentrations ranging from 1 X 10(-10) to 1 X 10(-5) M. Nonglucocorticoid sex hormones failed to inhibit tumoricidal activity in this system under identical culture conditions. Inhibition was most effective if the glucocorticoids were added simultaneously with the priming and triggering signals (rIFN-gamma and But-LPS); however, if the glucocorticoids were added 24 hr after the signals were provided to the cultures, suboptimal inhibition was observed. Experiments that dissociated the priming phase of activation from the triggering phase showed that glucocorticoids inhibited both the rIFN-gamma-induced priming stage as well as the But-LPS-induced triggering stage of activation. These observations provide evidence that glucocorticoids, but not other steroid hormones, inhibit the activation of macrophages to a fully tumoricidal state by interfering with either the priming or triggering signals in this two-signal model of macrophage activation. 相似文献
10.
PPARs调控巨噬细胞的活化与功能 总被引:1,自引:0,他引:1
巨噬细胞是先天性防御病原体的关键组分,它参与炎症的发生和消退,同时也参与了组织的修复。巨噬细胞的多种功能通过不同的活化状态完成,即从经典活化状态到替代性活化状态,再到失活状态。巨噬细胞活化的失调与代谢、炎症和免疫病变有关,调节蛋白控制巨噬细胞的活化可作为新的治疗靶点。主要综述过氧化物酶体增殖物激活受体(PPARs)调控巨噬细胞活化的作用。 相似文献
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《Redox report : communications in free radical research》2013,18(2-3):98-100
AbstractNeopterin and the reduced form, 7,8-dihydroneopterin (78NP) are pteridines released from macrophages when stimulated with interferon-γ (IFN-γ) in vivo.1,2 The role of 78NP in inflammatory response is unknown, though neopterin has been used clinically as a marker of immune cell activation due to its very fluorescent nature. 78NP is a potent antioxidant in a number of in vitro systems,3–5 leading to the suggestion that it has a role in protecting macrophages from free radical damage during inflammation.3 相似文献
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Toll receptors,CD14, and macrophage activation and deactivation by LPS 总被引:17,自引:0,他引:17
This review will focus on the molecular mechanisms of macrophage activation and desensitization by bacterial lipopolysaccharide (LPS). The most recent advances in the understanding of the function of the LPS receptor complex and its role in the development of the septic shock syndrome and endotoxin tolerance will be discussed. 相似文献
14.
Metabolic activation of hydroquinone by macrophage peroxidase 总被引:2,自引:0,他引:2
Lysates from macrophages, cells involved in hematopoiesis and immunological responses, catalyzed the metabolic activation of the benzene metabolite, hydroquinone, to protein-binding compounds and to free 1,4-benzoquinone. This reaction is mediated by a peroxidase since activation was dependent upon H2O2 and was prevented by the inhibitors aminotriazole and azide. Activation of hydroquinone was independent of HO. radicals since protein binding occurred in the presence of the HO. scavengers mannitol and dimethyl sulfoxide. In reactions with macrophage lysates, phenol, another hepatic metabolite of benzene, stimulated the production of 1,4-benzoquinone as well as the amount of hydroquinone equivalents bound to protein in a dose-dependent manner. Addition of cysteine to incubations with macrophage lysates resulted in a dose-dependent decrease in hydroquinone equivalents bound to protein. At 100 microM cysteine, protein binding was inhibited by 63% and this decrease was recovered as the monocysteine-hydroquinone conjugate. Macrophages catalyzed the arachidonic acid-mediated activation of hydroquinone to metabolites which bound to cellular macromolecules. This activation was inhibited by indomethacin indicating the action of prostaglandin synthase in hydroquinone metabolism by macrophages. The results of these experiments demonstrate that macrophage peroxidase catalyzes the metabolic oxidation of hydroquinone to 1,4-benzoquinone and that 1,4-benzoquinone and/or its semiquinone intermediate are binding to protein and cysteine. Hydroquinone activation by macrophages and subsequent macromolecular binding may be associated with the immunologic and hematopoietic toxicity of benzene. 相似文献
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Yusei Yamamoto Shigeki Nagao Atsushi Tanaka Toshitaka Koga Kaoru Onoue 《Biochemical and biophysical research communications》1978,80(4):923-928
N-acetylmuramyl-L-alanyl-D-isoglutamine, a synthetic compound which is known to have a minimal effective structure for an adjuvant activity of cell wall peptidoglycans, was found to inhibit the migration of normal macrophages. It was shown that the inhibition was neither due to cytotoxic or agglutinating effect of the muramyl dipeptide on macrophages nor due to lymphokine production uopn stimulation of lymphocytes by the muramyl dipeptide. 相似文献
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Mediator-induced macrophage activation, as shown by enhanced cytotoxicity for tumor, requires macrophage surface fucose and sialic acid 总被引:1,自引:0,他引:1
Macrophage-activating factor (MAF) activates macrophages so that their cytotoxic capacity is enhanced. This effect of MAF is inhibited by removing fucose from the macrophage cell surface by incubation with fucosidase, or by removing sialic acid by treatment with neuraminidase. After incubation with fucosidase or neuraminidase the average inhibition of cytotoxicity was 92 and 73%, respectively. β-Galactosidase had no effect. Addition of the specific products, fucose or sialic acid, to the incubation mixture of macrophages and enzyme blocked the effect of the enzymes. Taken together these observations indicate that macrophage surface fucose and sialic acid are essential for the interaction of MAF with macrophages which results in enhanced cytotoxicity for tumor cells. 相似文献
18.
Kinetics and mechanisms of macrophage activation by heat-killed Corynebacterium anaerobium (CA) in mice were investigated. The carbon clearance test revealed that the function of the reticuloendothelial system rose markedly on the 4th day after a single intravenous injection of CA and continued in a highly enhanced state until the 14th day. This activity declined gradually and dropped to a normal level around the 21st day. On the other hand, both lysosomal enzymes, beta-glucuronidase and acic phosphatase, of peritoneal macrophages decreased after the CA injection and then recovered, taking an almost inverse course to the function of the reticuloendothelial system. These results might be attributable to possible extracellular secretion of the lysosomal enzymes in accordance with macrophage activation by CA. A remarkable cytotoxicity of peritoneal macrophages, examined in vitro against L 929 cells, was detected on the 4th day following intraperitoneal administration of CA. It was maintained up to the 14th day and then declined rapidly. The mechanisms of macrophage activation by CA were also examined in vitro. CA-homogenate, heat-killed CA disrupted with an ultrasonicator, directly activated thioglycollate-induced macrophages. The macrophages were aslo activated by simultaneous treatment with both CA-homogenate and CA-sensitized spleen cells. Furthermore, the supernatant obtained from the culture of CA-sensitized spleen cells with CA-homogenate was capable of inducing activation of the macrophages. Conversely, the culture supernatant of spleen cells from CA-immunized athymic nude mice with CA-homogenate was unable to activate them. It was ascertained from the above-mentioned results that macrophages are activated initially by direct action of CA in a nonspecific way and subsequently by a soluble factor elaborated by CA-sensitized lymphocytes in an immunological way. 相似文献
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Lakics V Medvedev AE Okada S Vogel SN 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(5):2729-2737
The antiapoptotic molecule Bcl-xL has been implicated in the differentiation and survival of activated macrophages in inflammatory conditions. In this report, the role of Bcl-xL in LPS-induced cytokine gene expression and secretion was studied. Bcl-xL-transfected RAW 264 macrophages were protected from gliotoxin-induced apoptosis, indicating the presence of functional Bcl-xL. Overexpression of Bcl-xL in this macrophage cell line was also associated with a marked inhibition of LPS-induced TNF-alpha, JE/monocyte chemoattractant protein 1, and macrophage inflammatory protein 2 secretion. Inhibition of LPS-induced cytokine secretion was paralleled by a decrease in levels of steady-state mRNA for the above cytokines and for IL-1beta. Decreased production of TNF-alpha in Bcl-xL transfectants was not due to increased mRNA degradation, as the mRNA half-lives were the same in Bcl-xL transfectants and control macrophages. Although the composition of NF-kappaB complexes detected by EMSA and supershift analysis in nuclear lysates derived from Bcl-xL transfectants and control cells was indistinguishable, LPS-induced inhibitory kappaBalpha degradation, as well as NF-kappaB binding and AP-1 activation, were slightly decreased by ectopic expression of Bcl-xL. More strikingly, LPS-induced phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase was strongly repressed by Bcl-xL overexpression, offering a possible mechanism for the inhibition of LPS-induced cytokine production. These data provide the first evidence for a novel role for Bcl-xL as an anti-inflammatory mediator in macrophages. 相似文献