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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids are efficient antiinflammatory agents, and their effects include transcriptional repression of several cytokines and adhesion molecules. Whereas glucocorticoids down-regulate the expression of genes relevant during inflammation, nuclear factor (NF)-kappa B/Rel proteins function as important positive regulators of these genes. The expression of intercellular adhesion molecule-1 (ICAM-1), which plays an essential role in recruitment and migration of leukocytes to sites of inflammation, is also down-regulated by glucocorticoids. We found that a functional NF-kappa B site in the ICAM-1 promoter, which can be activated by either 12-O-tetradecanoylphorbol-13-acetate or tumor necrosis factor-alpha (TNF alpha), is also the target for glucocorticoids. In this report we present evidence that the ligand-activated glucocorticoid receptor (GR) is able to repress RelA-mediated activation of the ICAM-1 NF-kappa B site. Conversely, transcriptional activation by GR via a glucocorticoid response element is specifically repressed by RelA, but not by other NF-kappa B/Rel family members. Mutational analysis of GR demonstrates that the DNA binding domain and the ligand binding domain are required for the functional repression of NF-kappa B activation. Despite the importance of the DNA binding domain, we found that the transcriptional repression of NF-kappa B, mediated by GR, is not caused by binding of GR to the ICAM-1 NF-kappa B element, but by a physical interaction between the GR and RelA protein. The repressive effect of GR on NF-kappa B-mediated activation was not shared by other steroid/thyroid receptors. Only the progesterone receptor, which belongs to the same subfamily as GR and which possesses high homology with GR, was able to repress NF-kappa B-mediated transcription. These studies highlight a possible molecular mechanism that can explain the antiinflammatory effects of glucocorticoid treatment during inflammation.
Mol Endocrinol 1995 Apr
PMID:Negative cross-talk between RelA and the glucocorticoid receptor: a possible mechanism for the antiinflammatory action of glucocorticoids. 765 84

We have shown previously that transforming growth factor beta 1 (TGF-beta 1) is antimitotic for human fetal adrenal (HFA) cells in vitro and that this effect can be partially blocked by adrenocorticotropic hormone (ACTH). In the present study, we sought to determine whether ACTH might interfere with TGF-beta 1 action by means of reducing TGF-beta 1 binding to adrenal cells. We incubated adrenal cells with 50 pM 125I-labeled TGF-beta 1 for 15 min to 3 h at 4 degree C and found that the binding of 125I-labeled TGF-beta 1 increased with time and could be inhibited in a dose-dependent manner by non-labeled TGF-beta 1 (0.05-10 nM), but not with other relevant cytokines: IL6, TNF alpha,IGF-I, IGF-II, TGF-alpha, and EGF. Pretreatment of HFA cells with ACTH (0.009-900 nM) for 4-24 h significantly increased specific 125I-labeled TGF-beta 1 binding compared to that in untreated cells; maximal increases in binding were achieved with 0.9 nM ACTH. This effect of ACTH could be mimicked by treatment of adrenal cells with dibutyryl cAMP (1 mM) or forskolin (10 microM). Scatchard analysis of data from ACTH-treated cells suggest the presence of two populations of TGF-beta 1 binding sites with different affinity and capacity of binding for the ligand.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Endocrinol 1995 Apr 01
PMID:Receptor binding of transforming growth factor-beta by human fetal adrenal cells. 766 78

Cystic fibrosis (CF) is characterized by a dramatic neutrophil recruitment and repeated Pseudomonas infections in the lungs. To evaluate cytokine releasibility by airway epithelial cells in the context of CF, we studied primary nasal epithelial cells isolated from the upper airways and continuous epithelial cell lines from normal and CF subjects. Relatively low levels of interleukin (IL)-8, IL-6, and granulocyte/macrophage colony-stimulating factor (GM-CSF) were produced spontaneously by primary epithelial cells (< 50 pg/10(6) cells) and higher levels of colony-stimulating factor-1 (CSF-1) (1 to 2 ng/10(6) cells). Cells were stimulated with substances that are likely to be present in the inflamed lungs of CF patients-namely, the proinflammatory monokines IL-1 and tumor necrosis factor-alpha (TNF alpha) as well as neutrophil elastase and bacterial products from Pseudomonas (mucoid exopolysaccharide [MEP] and rhamnolipids). Both IL-1 and TNF alpha induced a dose-dependent release of IL-6 (5 to 10 ng/10(6) cells) and GM-CSF (2 to 3 ng/10(6) cells) by primary epithelial cells from eight normal volunteers. The TNF alpha/IL-1-stimulated GM-CSF release was blocked by the addition of 1 microM dexamethasone, whereas basal CSF-1 release was unaffected. Neutrophil elastase was a potent inducer of IL-8 and GM-CSF both in primary epithelial cells and in cell lines. Dexamethasone (1 microM) did not inhibit elastase-induced IL-8 release in either normal or CF epithelial cells. Rhamnolipids and MEP were found to stimulate the copious release of IL-8, GM-CSF, and IL-6 from epithelial cells, in a steroid-sensitive fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1993 Oct
PMID:Release of interleukin-8, interleukin-6, and colony-stimulating factors by upper airway epithelial cells: implications for cystic fibrosis. 769 Nov 10

Tumor necrosis factor alpha (TNF-alpha) is a candidate human immunodeficiency virus type 1-induced neurotoxin that contributes to the pathogenesis of AIDS dementia complex. We report here on the effects of exogenous TNF-alpha on SK-N-MC human neuroblastoma cells differentiated to a neuronal phenotype with retinoic acid, TNF-alpha caused a dose-dependent loss of viability and a corresponding increase in apoptosis in differentiated SK-N-MC cells but not in undifferentiated cultures. Importantly, intracellular signalling via TNF receptors, as measured by activation of the transcription factor NF-kappa B, was unaltered by retinoic acid treatment. Finally, overexpression of bcl-2 or crmA conferred resistance to apoptosis mediated by TNF-alpha, as did the addition of the antioxidant N-acetylcysteine. These results suggest that TNF-alpha induces apoptosis in neuronal cells by a pathway that involves formation of reactive oxygen intermediates and which can be blocked by specific genetic interventions.
Mol Cell Biol 1995 May
PMID:Tumor necrosis factor alpha-induced apoptosis in human neuronal cells: protection by the antioxidant N-acetylcysteine and the genes bcl-2 and crmA. 773 19

The nature of the stimuli driving autoantibody production in systemic lupus erythematosus (SLE) is unclear, but cytokines are believed to play an important role. Since cytokines primarily appear to act locally at the tissue level, we analysed mRNA expression of several cytokines (IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-10, IFN gamma, TNF alpha, TNF beta and TGF beta 1) in the lymph nodes of lupus-prone mice, in models of early onset disease. We constructed a multispecific competitor fragment that allowed quantification of these cytokine transcripts by competitive PCR assay. The results reveal considerable overexpression of IL-1 beta, IL-10 and IFN gamma transcripts in SLE-prone MRL-lpr/lpr (MRL/l) and BXSB male (BXSBm) mice, but with some strain differences. IFN gamma was most markedly augmented in MRL/l mice (in some cases over 100-fold greater than control mice), IL-1 beta was most severely overexpressed in BXSBm mice while IL-10 was equally increased in both strains. In addition, TGF beta 1 expression was moderately elevated in the lymph nodes of BXSBm (but not MRL/l) mice. We found no abnormality in the expression of the other cytokines. Cytokine transcript levels were only slightly altered at 4 weeks of age, but were elevated from 10 to 22 weeks of age. The latter phase corresponds to a period where lupus-like disease escalates, resulting in frequent mortality. Interestingly, our results do not reveal a clear Th1 or Th2 cytokine expression pattern in these lupus-prone mice. IL-1 beta, IFN gamma and IL-10 are pleiotropic cytokines with pro-inflammatory and B-cell stimulatory effects. These results point to certain cytokines as potential targets for immunotherapy in lupus.
Mol Immunol 1995 May
PMID:Quantitative polymerase chain reaction analysis reveals marked overexpression of interleukin-1 beta, interleukin-1 and interferon-gamma mRNA in the lymph nodes of lupus-prone mice. 778 52

4-Deoxypyridoxine (4-DPD) is a potent antagonist of Vitamin B6 coenzyme which inhibits IL-1, lymphocyte proliferation and has demonstrated that tolerance to skin grafts can be induced by administering splenic cells to pyridoxine-deficient mice. Chronic inflammation induced by dorsal injections of 200 microliters of a 1:40 saturated crystal solution of potassium permanganate (KMnO4) in mice treated or untreated with 4-DPD (400 micrograms/dose), has been investigated. After 7 days all mice developed a subcutaneous granulomatous tissue indicative of a chronic inflammatory response, at the site of injection. KMnO4-treated mice injected intraperitoneally with 4-DPD (400 micrograms/dose) on 5 consecutive days (the first at the same time of induction of the granuloma) show a significant decrease in size and weight of granuloma when compared to mice not treated with 4-DPD (Controls). In addition, in all mice treated with 4-DPD there was a strong inhibition of TNF alpha in serum (P < 0.01) and in supernatant fluids (P < 0.05) from minced granuloma, while IL-6 was inhibited in the supernatant fluids (P < 0.05) of minced granulomas but was not detected in the serum of treated and untreated mice. In this study we show for the first time the antiinflammatory effect of 4-DPD on chronic inflammation and the inhibitory effect of TNF and IL-6 generation in supernatant fluids from minced granulomas.
Mol Cell Biochem 1994 Jul 13
PMID:4-Deoxypyridoxine inhibits chronic granuloma formation induced by potassium permanganate in vivo. 785 32

Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional, proinflammatory cytokine that is capable of activating a diverse number of target genes within multiple cell types. Little information is known regarding the role of TNF-alpha in the regulation of human airway mucin hypersecretion and MUC-2 gene expression. To assess the effect of TNF-alpha exposure on mucin secretion, human airway organ cultures and primary cultures of human airway epithelial cells were stimulated with 20 ng/ml of recombinant human TNF-alpha and mucin secretion quantitated by an enzyme-linked immunosorbent assay using a specific monoclonal antibody directed against human airway mucin. Significant increases in mucin secretion from human airway organ cultures were initially detected at 1 h, peaked at 8 h, and persisted for 24 h. The TNF-alpha-mediated mucin hypersecretion at 8 h was concentration dependent. Significant increases in mucin secretion from primary cultures of human airway epithelial cells were initially detected at 4 h, peaked at 48 h, and persisted for 72 h after stimulation with 20 ng/ml of recombinant human TNF-alpha. The TNF-alpha-mediated mucin hypersecretion at 48 h from primary cultures of human airway epithelial cells was inhibited by coincubation with soluble 55 kD, type I TNF receptors. Using reverse transcription-polymerase chain reaction and a human pulmonary mucoepidermoid carcinoma cell line (NCI-H292), increases in MUC-2 steady-state mRNA levels were first detectable after 30 min of TNF-alpha stimulation and persisted for 24 h. Cycloheximide did not inhibit TNF-alpha-mediated MUC-2 mRNA expression at 1 h, suggesting that new protein translation was not required.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Feb
PMID:Tumor necrosis factor-alpha induces mucin hypersecretion and MUC-2 gene expression by human airway epithelial cells. 786 17

The reverse transcription polymerase chain reaction (RT-PCR) was used to assess the induction of mRNA of the proinflammatory cytokines IL-1 beta, IL-6 and TNF alpha in the spleen, pituitary, hypothalamus and hippocampus of mice after an intraperitoneal injection of lipopolysaccharide (LPS, 10 micrograms/mouse). The kinetics of cytokine gene expression induced by peripheral LPS in the pituitary and brain structures were different from that observed in the spleen. For IL-1 beta the dose-response curve was also measured and also found to be different. These results support the idea that one pathway by which peripheral immune stimuli affect brain functions includes local synthesis of proinflammatory cytokines in certain brain structures.
Brain Res Mol Brain Res 1994 Nov
PMID:Peripheral administration of lipopolysaccharide induces the expression of cytokine transcripts in the brain and pituitary of mice. 787 46

The monocyte chemotactic protein-1 (MCP-1) is a 76 amino acid protein that specifically attracts monocytes. The expression of MCP-1 gene can be induced by lipopolysaccharides (LPS), phorbol esters (TPA) and several cytokines. However, how they regulate MCP-1 gene expression is not known. We tested whether the two putative TPA-responsive elements (TREs) and one kappa B enhancer-like region found in the MCP-1 promoter region, are involved in this regulation of MCP-1 gene expression. The 5' untranslated region of MCP-1 gene was linked to chloramphenicol acetyl transferase (CAT) reporter gene and transfected into human glioblastoma cells in which endogenous MCP gene expression was found to be stimulated by TPA and tumor necrosis factor-alpha (TNF-alpha). The 128 bp 5'-flanking region containing one TRE was adequate for basal promoter activity but the presence of both TREs in the MCP-1 promoter region were needed to give TPA responsive enhancement (2.5 fold) of expression of the marker gene. Mutations in either of the TRE's could abolish the TPA induction of CAT expression. Replacement of the kappa B enhancer-like element with a TRE-like sequence caused a 10-fold enhancement of CAT expression by TPA treatment. Random mutation of kappa B enhancer-like element did not affect CAT expression or its TPA induction. None of the MCP promoter constructs showed significant increase in CAT expression by treatment with tumor necrosis factor-alpha (TNF-alpha). This result suggested that the TNF regulation of MCP-1 gene involves other parts of the gene besides the proximal 5' flanking region.
Mol Cell Biochem 1994 Dec 21
PMID:Functional role of the cis-acting elements in human monocyte chemotactic protein-1 gene in the regulation of its expression by phorbol ester in human glioblastoma cells. 789 69

We studied the effect of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the cytotoxic action of TNF on MCF-7 human breast cancer cells and on adult bovine aortic endothelial cells. 1,25(OH)2D3 increased the effect of TNF on MCF-7 cells but not on endothelial cells over a wide TNF concentration range. At a suboptimal concentration (1 ng/ml) the potentiation was twofold. The effect of 1,25(OH)2D3 was specific, dose-dependent and apparent at a physiological concentration (0.1 nM) of the hormone. The potentiating effect of 1,25(OH)2D3 on TNF action was abolished by cycloheximide indicating that their interaction requires protein synthesis. Addition of 1,25(OH)2D3 13 h after TNF in a 28-h assay was sufficient to induce its full potentiating effect indicating that the hormone modulates a late event in the cytokine's action. These data suggest that some of the in vivo antitumor effects of 1,25(OH)2D3 may be due to an increase in the anticancer activity of the immune system.
Mol Cell Endocrinol 1994 Dec
PMID:1,25-Dihydroxyvitamin D3 potentiates the cytotoxic effect of TNF on human breast cancer cells. 789 2


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