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Amyloid beta-peptide activates nuclear factor-kappa B through an N-methyl-D-aspartate signaling pathway in cultured cerebellar cells

KAWAMOTO, E. M.; LEPSCH, L. B.; BOAVENTURA, M. F. C.; MUNHOZ, C. D.; LIMA, L. S.; YSHII, L. M.; AVELLAR, M. C. W.; Curi, Rui; MATTSON, M. P.; SCAVONE, C.
Fonte: WILEY-LISS Publicador: WILEY-LISS
Tipo: Artigo de Revista Científica
Português
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55.83%
Amyloid P-peptide (A beta) likely causes functional alterations in neurons well prior to their death. Nuclear factor-kappa B (NF-kappa B), a transcription factor that is known to play important roles in cell survival and apoptosis, has been shown to be modulated by A beta in neurons and glia, but the mechanism is unknown. Because A beta has also been shown to enhance activation of N-methyl-D-aspartate (NMDA) receptors, we investigated the role of NMDA receptor-mediated intracellular signaling pathways in A beta-induced NF-kappa B activation in primary cultured rat cerebellar cells. Cells were treated with different concentrations of A beta 1-40 (1 or 2 mu M) for different periods (6, 12, or 24 hr). MK-801 (NMDA antagonist), manumycin A and FTase inhibitor 1 (farnesyltransferase inhibitors), PP1 (Src-family tyrosine kinase inhibitor), PD98059 [mitogen-activated protein kinase (MAPK) inhibitor], and LY294002 [phosphatidylinositol 3-kinase (PI3-k) inhibitor] were added 20 min before A beta treatment of the cells. A beta induced a time- and concentration-dependent activation of NF-kappa B (1 mu M, 12 hr); both p50/p65 and p50/p50 NF-kappa B dimers were involved. This activation was abolished by MK-801 and attenuated by manumycin A, FTase inhibitor 1...

Lipopolysaccharide and interleukin 1 augment the effects of hypoxia and inflammation in human pulmonary arterial tissue.

Ziesche, R; Petkov, V; Williams, J; Zakeri, S M; Mosgöller, W; Knöfler, M; Block, L H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 29/10/1996 Português
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55.84%
The combined effects of hypoxia and interleukin 1, lipopolysaccharide, or tumor necrosis factor alpha on the expression of genes encoding endothelial constitutive and inducible nitric oxide synthases, endothelin 1, interleukin 6, and interleukin 8 were investigated in human primary pulmonary endothelial cells and whole pulmonary artery organoid cultures. Hypoxia decreased the expression of constitutive endothelial nitric oxide synthase (NOS-3) mRNA and NOS-3 protein as compared with normoxic conditions. The inhibition of expression of NOS-3 corresponded with a reduced production of NO. A combination of hypoxia with bacterial lipopolysaccharide, interleukin 1 beta, or tumor necrosis factor alpha augmented both effects. In contrast, the combination of hypoxia and the inflammatory mediators superinduced the expression of endothelin 1, interleukin 6, and interleukin 8. Here, we have shown that inflammatory mediators aggravate the effect of hypoxia on the down-regulation of NOS-3 and increase the expression of proinflammatory cytokines in human pulmonary endothelial cells and whole pulmonary artery organoid cultures.

Interleukin-1 beta modulates the growth and phenotype of neonatal rat cardiac myocytes.

Thaik, C M; Calderone, A; Takahashi, N; Colucci, W S
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1995 Português
Relevância na Pesquisa
55.84%
Mononuclear cell infiltration and local cytokine elaboration are hallmarks of inflammatory and immunologic heart diseases. To test the hypothesis that cytokines can modulate cardiac myocyte growth and phenotype, myocytes cultured from neonatal rat hearts were exposed to IL-1 beta, an inflammatory cytokine prevalent in myocardial inflammation. IL-1 beta (2 ng/ml, 24 h) increased [3H]leucine incorporation by 30 +/- 4% (P < 0.001, n = 29) and net cellular protein content by 20 +/- 4% (P < 0.001, n = 27), but had no effect on DNA synthesis. Northern hybridization showed that IL-1 beta increased prepro-atrial natriuretic factor (ANF) mRNA (5.8 +/- 1.5-fold, P < 0.01, n = 13) and beta-myosin heavy chain (beta-MHC) mRNA (> 10-fold, n = 4), and decreased mRNA levels for sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2) (-46 +/- 7%; P < 0.001; n = 11), calcium release channel (CRC) (-65 +/- 11%, P < 0.001, n = 8) and voltage-dependent calcium channel (VDCC) (-53 +/- 7%, P < 0.001, n = 8). NG-monomethyl-L-arginine (1 mM), an inhibitor of nitric oxide (NO) synthesis, did not inhibit the IL-1 beta-induced protein synthesis or changes in mRNA levels. In ventricular myocardium obtained from adult rats treated with lipopolysaccharide (4 mg/kg intraperitoneally 18 h) to stimulate systemic cytokine production...

Induction of tumor necrosis factor (TNF) and interleukin-1 (IL-1) by Pseudomonas aeruginosa and exotoxin A-induced suppression of lymphoproliferation and TNF, lymphotoxin, gamma interferon, and IL-1 production in human leukocytes.

Staugas, R E; Harvey, D P; Ferrante, A; Nandoskar, M; Allison, A C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1992 Português
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Pseudomonas aeruginosa is a dominant pathogen in infection in cystic fibrosis. This bacterium is thought to play a major role in the chronic bronchial infection-induced pathophysiology. Our data showed that whole formalin-fixed heat-killed P. aeruginosa was mitogenic for human lymphocytes and induced production of substantial amounts of tumor necrosis factor alpha (TNF) in peripheral blood mononuclear leukocytes in cultures. Significant amounts of TNF were produced at 10(3) bacteria per 2 x 10(5) mononuclear leukocytes. Treatment of P. aeruginosa with polymixin B did not affect its ability to stimulate TNF production, suggesting that bacterial lipopolysaccharide is not involved. P. aeruginosa, however, did not stimulate production of the T-cell lymphokine lymphotoxin (TNF beta). Exotoxin A, considered to be an important virulence factor produced by P. aeruginosa, did not stimulate either lymphoproliferation or production of TNF. In fact, this toxin, at nontoxic concentrations, was found to depress lymphoproliferation induced by phytohemagglutinin and Staphylococcus aureus and decreased production of TNF, lymphotoxin, and gamma interferon in either lymphocytes or macrophages. This toxin similarly inhibited the production of interleukin-1 beta (IL-1 beta) and IL-1 alpha...

Modulation of interleukin-1 beta RNA in monocytic cells infected with human immunodeficiency virus-1.

Yamato, K; el-Hajjaoui, Z; Simon, K; Koeffler, H P
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1990 Português
Relevância na Pesquisa
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The effect of HIV-1 infection on cytokine levels was studied in monocytic cells by using Northern blotting analysis. Monoblasts (THP-1, U937) did not express IL-1 beta RNA even if the cells were infected with HIV-1. After exposure to LPS (10 micrograms/ml) and 12-O-tetradecanoylphorbol-13-acetate (TPA, 100 nM) for 12 h, these HIV-1-infected monoblasts accumulated 8-15-fold greater levels of IL-1 beta RNA as compared with their HIV-1-uninfected counterparts that were similarly stimulated. In contrast, levels of RNAs coding for monocyte-colony-stimulating factor (M-CSF) and tumor necrosis factor-alpha (TNF alpha) were elevated less than twofold in the HIV-1-infected cells as compared with HIV-1-uninfected cells after their stimulation with LPS and TPA. Inhibition of new protein synthesis did not block the marked accumulation of IL-1 beta RNA produced by exposure to LPS and TPA in the HIV-1-infected cells. Time-course experiments showed that the maximal levels of IL-1 beta RNA occurred at 12 and 24 h after LPS and TPA stimulation of the HIV-1-infected and uninfected U937 cells, respectively. Studies of stability of RNA using actinomycin D showed that IL-1 beta RNA was equally stable in infected and uninfected U937 cells after their stimulation with TPA and LPS. Taken together...

Interleukin-1 expression by neutrophils in rheumatoid arthritis.

Quayle, J A; Adams, S; Bucknall, R C; Edwards, S W
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /11/1995 Português
Relevância na Pesquisa
55.83%
OBJECTIVE--To determine if neutrophils from blood and synovial fluid of patients with rheumatoid arthritis and other joint arthropathies express interleukin-1 beta mRNA. METHODS--RNA was isolated from neutrophils from patient and control blood, and synovial fluid of patients, probed in northern blots, and quantified by densitometry. It was also isolated and analysed from control blood neutrophils after incubation in vitro with granulocyte macrophage colony stimulating factor (GM-CSF). RESULTS--Neutrophils from the synovial fluid of patients with rheumatoid arthritis contained low levels of mRNA for interleukin-1 beta--between 0.1 and 2% of those observed during stimulation of control neutrophils with GM-CSF for one hour. Higher levels (4-40% of the maximal GM-CSF values) were observed in blood neutrophils from patients with rheumatoid arthritis. CONCLUSIONS--Neutrophils contribute to the cytokine network in rheumatoid arthritis. In some circumstances, activation of transcription may occur within the circulation of these patients.

Interleukin-1 and lipid metabolism in the rat.

Argilés, J M; Lopez-Soriano, F J; Evans, R D; Williamson, D H
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/05/1989 Português
Relevância na Pesquisa
55.83%
Intravenous administration of a single dose (20 micrograms) of recombinant interleukin-1-beta to virgin, lactating and litter-removed rats rapidly decreased intestinal lipid absorption in all groups. In vivo, oxidation of [14C]triolein to 14CO2 was also significantly decreased by interleukin-1. In addition, the cytokine decreased [14C]lipid accumulation in the mammary gland of lactating rats and in the adipose tissue of virgin and litter-removed rats. The decrease in lipid uptake in the interleukin-treated rats was accompanied by hypertriglyceridaemia; however, there was no significant decrease in tissue lipoprotein lipase activity, except in heart from lactating rats. In contrast, interleukin-1 administration had no effect on lipogenesis in liver, white or brown adipose tissue of virgin rats fed on glucose. These results suggest that interleukin-1 profoundly affects lipid metabolism by delaying intestinal absorption and decreasing tissue uptake.

Unopposed interleukin-1 is necessary for increased plasma cytokine and eicosanoid levels to develop in severe sepsis.

Slotman, G J; Quinn, J V; Wry, P C; Brathwaite, C E; Friedman, B M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /07/1997 Português
Relevância na Pesquisa
55.85%
OBJECTIVE: The purpose of the study was to identify the changes in plasma prostaglandin, leukotriene, and cytokine levels during clinical severe sepsis for which interleukin-1 was necessary. SUMMARY BACKGROUND DATA: Circulating prostaglandins, leukotrienes, and cytokines have been implicated as causative agents of systemic inflammation due to sepsis. However, interactions between interleukin-1 and the other cytokine and eicosanoid mediators of severe sepsis are not well-defined. METHODS: As part of two sequential multisite, prospective, randomized, double-blind, placebo-controlled clinical trials, 37 patients with severe sepsis received interleukin-1 receptor antagonist (IL-1ra) 100-mg bolus followed by 2 mg/kg per hour intravenously for 72 hours (n = 20) or placebo (n = 17). Plasma thromboxane B2 (TxB2), prostaglandin 6-keto-F1alpha (PGI), leukotriene B4 (LTB4), leukotriene C4D4E4 (LTC4D4E4), interleukin-1 beta (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were measured by enzyme-linked immunosorbent assay before study drug infusion (baseline) and at 24, 48, and 72 hours after the beginning of the study drug infusion. RESULTS: Differences between placebo and IL-1ra for plasma LTB4 were not significant, but only IL-1ra LTB4 increased from baseline. Plasma TxB2...

Effect of lisofylline and pentoxifylline on the bacterial-stimulated production of TNF-alpha, IL-1 beta IL-10 by human leucocytes.

van Furth, A M; Verhard-Seijmonsbergen, E M; van Furth, R; Langermans, J A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1997 Português
Relevância na Pesquisa
55.85%
The present study concerns the effect of the xanthine derivates lisofylline (LSF) and pentoxifylline (PTX) on the production of pro-inflammatory cytokines tumour-necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) and the de-activating cytokine interleukin-10 (IL-10) by human leucocytes during stimulation with lipopolysaccharide (LPS), heat-killed Gram-negative bacteria (GNB) or Gram-positive bacteria (GPB). The production of TNF-alpha and IL-1 beta by leucocytes stimulated with LPS, Haemophilus influenzae type b (Hib) or Streptococcus pneumoniae was inhibited by both drugs. The production of IL-10 by leucocytes stimulated with LPS and Hib was inhibited by both xanthine derivates only at 48 hr. However, incubation of leucocytes with S. pneumoniae in the presence of LSF or PTX stimulated the production of IL-10 about four- and twofold at 24 hr and 48 hr, respectively. In all instances, the extent of inhibition or enhancement of cytokine production by LSF or PTX was equal. The divergent effects of xanthine derivates on the IL-10 production indicate the existence of distinct intracellular pathways depending on whether leucocytes are stimulated by GPB or GNB.

Regulation of interleukin-1 and tumour necrosis factor gene expression in myelomonocytic cell lines by 1,25-dihydroxyvitamin D3.

Bhalla, A K; Paavonen, T; Williams, M M; Delves, P J; Lydyard, P M
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1991 Português
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55.85%
1,25-dihydroxyvitamin D3[1,25-(OH)2D3] is capable of regulating cells in the immune system and affects cytokine production by both T lymphocytes and by monocytes. We examined the effects of 1,25-(OH)2D3 on the regulation of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) genes in HL-60 and U937 cells. 1,25-(OH)2D3 alone only induced low level expression of the genes for these cytokines. Phorbol 12-myristate 13-acetate (PMA) strongly induced the transcription of these genes, whilst the addition of 1,25-(OH)2D3 to PMA-stimulated cells caused a further dose-dependent synergistic increase in the mRNA for both cytokines in U937 cells. In PMA-stimulated HL-60 cells, 1,25-(OH)2D3 increased the mRNA for IL-1 beta but not that for TNA-alpha, These differences may be related to the different stage of myeloid differentiation in HL-60 and U937 cells.

TGF-beta and IL-1 beta act in synergy to enhance IL-6 and IL-8 mRNA levels and IL-6 production by human retinal pigment epithelial cells.

Kuppner, M C; McKillop-Smith, S; Forrester, J V
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /02/1995 Português
Relevância na Pesquisa
55.85%
Cytokines produced by human retinal pigment epithelial (RPE) cells may function as important regulators of intraocular inflammation. We investigated the effect of transforming growth factor-beta (TGF-beta) on interleukin-1 beta (IL-1 beta) induction of IL-6 and IL-8 mRNA levels and protein production by human RPE cells. Both TGF-beta and IL-1 beta alone induce IL-6 mRNA and IL-6 production in human RPE cells and synergize to enhance IL-6 mRNA levels and IL-6 production over a range of TGF-beta (0.1-10 ng/ml) and IL-1 beta concentrations (5-500 U/ml). TGF-beta was also found to enhance IL-1 beta induction of IL-8 mRNA levels at lower IL-1 beta concentrations (50 U/ml) but had no effect at higher IL-1 beta concentrations (500 U/ml). However, TGF-beta had no synergistic effect on IL-1 beta induction of IL-8 secretion. These results suggest that expression of IL-6 and IL-8 in human RPE cells is regulated by different transcriptional and translational mechanisms, and that RPE cells are important regulators of cytokine production within the ocular microenvironment.

In vitro modulation of interleukin-1 beta secretion by cultured rat doxorubicin-stimulated whole glomeruli and dissociated mesangial glomerular cells.

Bricio, T; Molina, A; Martin, A; Mampaso, F
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1994 Português
Relevância na Pesquisa
55.85%
Doxorubicin-stimulated whole rat glomeruli and dissociated mesangial and resident glomerular macrophage cells produced the release of interleukin (IL)-1 beta cytokine. This activity increased after the addition of lipopolysaccharide (LPS) or LPS plus indomethacin to the cultures. In the presence of WEB2086 [platelet-activating factor (PAF)-acether antagonist], this activity showed a drastic reduction, without modification after sodium furegrelate (thromboxane synthetase inhibitor) was added to the cultures. Our results also demonstrate that this IL-1 beta activity is mainly produced by glomerular-resident macrophage cells. These findings support the important role by both IL-1 beta and PAF-acether mediator factors, at the cellular level, in the rat model of doxorubicin-induced nephrosis.

Up-regulation of [3H]-des-Arg10-kallidin binding to the bradykinin B1 receptor by interleukin-1 beta in isolated smooth muscle cells: correlation with B1 agonist-induced PGI2 production.

Galizzi, J P; Bodinier, M C; Chapelain, B; Ly, S M; Coussy, L; Giraud, S; Neliat, G; Jean, T
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/1994 Português
Relevância na Pesquisa
55.84%
1. Binding of the specific bradykinin B1 receptor agonist, [3H]-des-Arg10-kallidin (-KD) was investigated in smooth muscle cells (SMC) isolated from rabbit mesenteric arteries (RMA). 2. [3H]-des-Arg10-KD specifically bound to interleukin-1 (IL-1)-treated RMA-SMC in a saturable fashion with an equilibrium dissociation constant (KD) of 0.3-0.5 nM. The number of binding sites per cell was 20,000-35,000. Kinins inhibited [3H]-des-Arg10-KD binding to RMA-SMC with an order of potency very similar to that observed in typical B1 specific bioassays: des-Arg9-bradykinin (BK) approximately KD >> BK. Furthermore, the B1 receptor antagonist [Leu8]des-Arg9-BK inhibited [3H]-des-Arg10-KD binding with an IC50 of 43 nM as expected for its effect at B1 receptors. The B2 receptor antagonists, NPC 567 and Hoe 140 only affected [3H]-des-Arg10-KD binding at very high concentrations (IC50 = 0.8 microM and IC50 > 10 microM, respectively). 3. Des-Arg9-BK (B1 agonist) and [Hyp3]Tyr(Me)8-BK (B2 agonist) did not induce prostacyclin (PGI2) production by RMA-SMC. Lipopolysaccharide (LPS) treatment of the cells did not affect the B1 agonist response whereas IL-1 beta treatment produced a 7 fold increase in des-Arg9-BK-stimulated PGI2 production. IL-1 beta also stimulated the response to B2 agonists. 4. Des-Arg9-BK-induced PGI2 secretion in IL-1-primed RMA-SMC was mediated by B1 receptors since it was inhibited by [Leu8]des-Arg9-BK (IC50 = 56-73 nM) but not by Hoe 140.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased interleukin-1 beta and fibronectin expression are early features of the development of the postcardiac transplant coronary arteriopathy in piglets.

Clausell, N.; Molossi, S.; Rabinovitch, M.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /06/1993 Português
Relevância na Pesquisa
55.85%
The mechanism causing intimal thickening in the postcardiac transplant coronary arteriopathy (PCTCA) is associated with interactions between inflammatory cells and vascular cells. Our previous studies related intimal thickening to fibronectin-dependent smooth muscle cell (SMC) migration into the subendothelium, and others have shown that cytokines, eg, interleukin (IL)-1 beta, up-regulate SMC fibronectin synthesis. In this study, we identified, in piglets, features compatible with early development of the PCTCA. Ultrastructure revealed increased SMC and inflammatory cells in the subendothelium. Immunohistochemistry showed major histocompatibility complex II presentation in the endothelium and adventitia, associated with infiltration of different subsets of inflammatory cells; increased IL-1 beta, particularly in the endothelium; and fibronectin, in the subendothelium and inner media, the latter confirmed by quantitative immunoelectron microscopy. In the PCTCA, increases in IL-1 beta and fibronectin could mediate adherence, transendothelial migration and trapping of inflammatory cells, and SMC migration into the subendothelium.

C5a stimulates secretion of tumor necrosis factor from human mononuclear cells in vitro. Comparison with secretion of interleukin 1 beta and interleukin 1 alpha

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/07/1988 Português
Relevância na Pesquisa
55.84%
We have demonstrated that purified C5a is a potent stimulus to human PBMC secretion of TNF-alpha, IL-1 beta, and IL-1 alpha, which proceeds in a dose-dependent fashion. At a given concentration of C5a, TNF-alpha and IL-1 beta secretion did not differ significantly; both were secreted in significantly greater quantity than IL-1 alpha. Clinical conditions such as Gram-positive and Gram-negative bacterial infections, trauma, and immune complex diseases activate complement. Through the mediation of TNF and IL-1 secreted in response to C5a, these diverse disorders can share common features of fever, coagulopathy, acute phase protein production, and disordered metabolism.

Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 beta and interleukin 6 appearance during lethal bacteremia

Fonte: The Rockefeller University Press Publicador: The Rockefeller University Press
Tipo: Artigo de Revista Científica
Publicado em 01/11/1989 Português
Relevância na Pesquisa
55.83%
Cytokines secreted in response to invading micro-organisms are important mediators of detrimental hemodynamic and metabolic changes in the host. To test whether cachectin/TNF plays a role in triggering release of other cytokines in the setting of infection, anesthetized baboons were passively immunized against systemic cachectin/TNF before infusion of a LD100 dose of live Escherichia coli. Bacteremia led to significant increases in circulating levels of cachectin/TNF, IL-1 beta, and IL-6. Although bacterial endotoxin/lipopolysaccharide is a potent stimulus for the synthesis and release of IL-1 and IL-6 in vitro, specific neutralization of cachectin/TNF in vivo with mAb pretreatment significantly attenuated both the IL-1 beta and the IL-6 responses despite fulminant overwhelming bacteremia. These data suggest that cachectin/TNF is essential for the initiation or amplification of IL-1 and IL-6 release during lethal gram-negative septic shock syndrome.

La Rapamycine inhibe l’expression de l’ARNm de l’ADAMTS-4 induit par les cytokines dans les chondrocytes articulaires

Khalifé, Sarah
Fonte: Université de Montréal Publicador: Université de Montréal
Tipo: Thèse ou Mémoire numérique / Electronic Thesis or Dissertation
Português
Relevância na Pesquisa
55.86%
Introduction: Durant la pathogenèse d’ostéoarthrose (OA), les cytokines pro-inflammatoires IL-1β (Interleukin-1 beta) et TNF-α (Tumor necrosis factor alpha) stimulent la dégradation des agrécanes par l’aggrécanase-1 ou ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motif). Ces cytokines peuvent stimuler plusieurs voies de signalisation conduisant ainsi à l’augmentation de l’expression des ADAMTS dans les chondrocytes humains. Les TIMPs (tissue inhibitor of metalloproteinases) présentent des inhibiteurs endogènes de l’ADAMTS. Nous avons démontré que la Rapamycine (un immunosuppresseur et un inhibiteur du mamalian target of Rapamycin (mTOR)) peut avoir des effets bénéfiques dans cette pathologie. Notre étude examine l’effet de la Rapamycine sur l’expression de l’ADAMTS-4 induit par les cytokines, son implication dans certaines voies de signalisation, et son effet sur l’expression du TIMP-3. Méthodes: Des chondrocytes normaux sont traités avec la Rapamycine seule ou stimulés aussi avec l’IL-1β et le TNF-α. Les effets de la Rapamycine sur l’expression de l’ADAMTS-4 et du TIMP-3 ont été étudiés par l’analyse RT-PCR et l’activité enzymatique a été étudiée par la technique d’ELISA. Les effets de la Rapamycine sur certaines voies de signalisation ont été étudiés par le Western blot. Résultats: Nous avons trouvé que la Rapamycine inhibe l’expression de l’ARNm de l’ADAMTS-4 induit par les cytokines pro-inflammatoires dans les chondrocytes humains. L’activité enzymatique de l’ADAMTS-4 induit par l’IL-1β a été légèrement diminuée par la Rapamycine. En plus...

Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms.

Kern, J A; Lamb, R J; Reed, J C; Daniele, R P; Nowell, P C
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /01/1988 Português
Relevância na Pesquisa
55.83%
Dexamethasone is known to have an inhibitory effect on IL-1 production. To determine the mechanism(s) of this inhibition, adherent human blood monocytes were stimulated with Escherichia coli lipopolysaccharide (LPS) (10 micrograms/ml) in the presence of dexamethasone. Nuclear transcription run-off assays showed that LPS induced IL-1 beta gene transcription two- to fourfold and that this induction was unaffected by dexamethasone exposure (10(-5) M). The lack of dexamethasone's transcriptional effects was further supported by the absence of any significant change in IL-1 beta mRNA accumulation between LPS-stimulated monocytes exposed or unexposed to dexamethasone, as determined by Northern blot analysis. Posttranscriptionally, dexamethasone was found to have multiple effects: slight prolongation of IL-1 beta mRNA half-life, moderate inhibition of translation of the IL-1 beta precursor, and profound inhibition of the release of IL-1 beta into the extracellular fluid. The data indicate that IL-1 beta is first translated as the 33,000-D pro-IL-1 beta protein, the predominant intracellular form, and the processed to a 17,500-D IL-1 beta protein before or during extracellular transport. The major inhibitory effects of dexamethasone appear to be directed at the translational and posttranslational steps involved in these events.

Mechanisms of stimulation of interleukin-1 beta and tumor necrosis factor-alpha by Mycobacterium tuberculosis components.

Zhang, Y; Doerfler, M; Lee, T C; Guillemin, B; Rom, W N
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /05/1993 Português
Relevância na Pesquisa
55.83%
The granulomatous immune response in tuberculosis is characterized by delayed hypersensitivity and is mediated by various cytokines released by the stimulated mononuclear phagocytes, including tumor necrosis factor-alpha (TNF alpha) and IL-1 beta. We have demonstrated that Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM), mycobacterial heat shock protein-65 kD, and M. tuberculosis culture filtrate, devoid of LPS as assessed by the Amebocyte Lysate assay, stimulate the production of TNF alpha and IL-1 beta proteins and mRNA from mononuclear phagocytes (THP-1 cells). The effect of LAM on the release of these cytokines was specific, as only LAM stimulation was inhibited by anti-LAM monoclonal antibody. Interestingly, we found that LAM and Gram-negative bacterial cell wall-associated endotoxin LPS may share a similar mechanism in their stimulatory action as demonstrated by inhibition of TNF alpha and IL-1 beta release by monoclonal antibodies to CD14. Anti-CD14 monoclonal antibody MY4 inhibited both TNF alpha and IL-1 beta release with LAM and LPS but no effect was observed with other mycobacterial proteins. An isotype antibody control did not inhibit release of cytokines under the same experimental conditions. M. tuberculosis and its components upregulated IL-1 beta and TNF alpha mRNAs in THP-1 cells. Nuclear run-on assay for IL-1 beta demonstrated that LAM increased the transcription rate. The induction of IL-1 beta was regulated at the transcriptional level...

Inhibition by tetranactin of interleukin 1 beta- and cyclic AMP-induced nitric oxide synthase expression in rat renal mesangial cells.

Kunz, D.; Walker, G.; Wiesenberg, I.; Pfeilschifter, J.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /08/1996 Português
Relevância na Pesquisa
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1. We have investigated whether tetranactin, a cyclic antibiotic produced by Streptomyces aureus with a molecular structure related to cyclosporin A, influences inducible nitric oxide synthase (iNOS; EC 1.14.13.39) induction in rat glomerular mesangial cells. 2. Previously we have shown that iNOS is expressed in renal mesangial cells in response to two principal classes of activating signals comprising inflammatory cytokines such as interleukin 1 (IL-1) or tumour necrosis factor alpha and agents that elevate cellular levels of cyclic AMP. Treatment of mesangial cells with IL-1 beta or the membrane-permeable cyclic AMP analogue, N6, 0-2'-dibutyryladenosine 3',5'-phosphate (Bt2 cyclic AMP) for 24 h induces iNOS activity measured as nitrite levels in cell culture supernatants by 44 fold or 33 fold, respectively. Incubation of mesangial cells with tetranactin inhibits IL-1 beta- and cyclic AMP-dependent production of nitrite in a dose-dependent fashion with IC50 values of 50 nM and 10 nM, respectively. 3. Western-blot analyses of mesangial cell extracts reveal that the inhibition of nitrite synthesis by tetranactin is due to a suppression of iNOS protein levels. This effect is preceded by a reduction of iNOS mRNA steady state levels as demonstrated by Northern blot analyses of total cellular RNA isolated from stimulated mesangial cells. 4. Thus...