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Post by Max on Jun 12, 2005 14:13:36 GMT -5
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Post by Max on Jun 12, 2005 14:14:15 GMT -5
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Post by Max on Jun 12, 2005 14:14:37 GMT -5
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Post by Max on Jun 12, 2005 14:15:08 GMT -5
J Immunol. 2004 Nov 1;173(9):5343-8. Related Articles, Links
Mechanisms of soluble cytokine receptor generation.
Levine SJ.
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. levines@nhlbi.nih.gov
Soluble cytokine receptors regulate inflammatory and immune events by functioning as agonists or antagonists of cytokine signaling. As such, they act within complex receptor systems that include signaling receptors, nonsignaling decoy receptors, receptor-associated proteins, and soluble receptor antagonists. Soluble cytokine receptors can be generated by several mechanisms, which include proteolytic cleavage of receptor ectodomains, alternative splicing of mRNA transcripts, transcription of distinct genes that encode soluble cytokine-binding proteins, release of full-length receptors within the context of exosome-like vesicles, and cleavage of GPI-anchored receptors. Furthermore, the important role of soluble cytokine receptors in regulating host defense mechanisms is evidenced by viruses that encode soluble homologues of mammalian receptors and thereby evade innate host immune responses via the sequestration of essential cytokines.
Publication Types:
Review
Review, Tutorial
PMID: 15494479 [PubMed - indexed for MEDLINE]
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Post by Max on Jun 17, 2005 15:30:03 GMT -5
Glia. 2005 Apr 1;50(1):21-31. Related Articles, Links
Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia.
Dheen ST, Jun Y, Yan Z, Tay SS, Ling EA.
Department of Anatomy, Molecular Neurobiology Laboratory, Faculty of Medicine, National University of Singapore, Singapore. antstd@nus.edu.sg
The release of proinflammatory mediators such as tumor necrosis factor-alpha (TNF-alpha) and nitric oxide by microglia has been implicated in neurotoxicity in chronic neurodegenerative diseases such as Alzheimer's disease. As all-trans-retinoic acid (RA) has been reported to exert anti-inflammatory actions in various cell types, we have examined its effects on the expression of TNF-alpha and inducible nitric oxide synthase (iNOS) in microglia activated by beta-amyloid peptide (Abeta) and lipopolysaccharide (LPS). Exposure of primary cultures of rat microglial cells to Abeta or LPS stimulated the mRNA expression level of TNF-alpha (6-116-fold) and iNOS (8-500-fold) significantly. RA acted in a dose-dependent manner (0.1-10 microM) by attenuating both TNF-alpha (29-97%) and iNOS (61-96%) mRNA expression in microglia exposed to Abeta or LPS. RA-induced inhibition of TNF-alpha and iNOS mRNA expression in activated microglia was accompanied by the concomitant reduction in release of iNOS and TNF-alpha proteins as revealed by nitrite assay and ELISA, respectively. The anti-inflammatory effects of RA were correlated with the enhanced expression of retinoic acid receptor-beta, and transforming growth factor-beta1 as well as the inhibition of NF-kappaB translocation. These results suggest that RA may inhibit the neurotoxic effect of activated microglia by suppressing the production of inflammatory cytokines and cytotoxic molecules. 2004 Wiley-Liss, Inc.
PMID: 15602748 [PubMed - indexed for MEDLINE]
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Post by Max on Jun 17, 2005 15:34:24 GMT -5
Mutat Res. 2004 Jul 13;551(1-2):199-211. Related Articles, Links
Molecular imaging of the transcription factor NF-kappaB, a primary regulator of stress response.
Carlsen H, Alexander G, Austenaa LM, Ebihara K, Blomhoff R.
Department of Nutrition, Faculty of Medicine, University of Oslo, P.O. Box 1046 Blindern, N-0316 Oslo, Norway.
A wide range of environmental stress and human disorders involves inappropriate regulation of NF-kappaB, including cancers and numerous inflammatory conditions. We have developed transgenic mice that express luciferase under the control of NF-kappaB, enabling real-time non-invasive imaging of NF-kappaB activity in intact animals. We show that, in the absence of stimulation, strong, intrinsic luminescence is evident in lymph nodes in the neck region, thymus, and Peyer's patches. Treating mice with stressors, such as TNF-alpha, IL-1alpha, or lipopolysaccharide (LPS) increases the luminescence in a tissue-specific manner, with the strongest activity observable in the skin, lungs, spleen, Peyer's patches, and the wall of the small intestine. Liver, kidney, heart, muscle, and adipose tissue exhibit less intense activities. Exposure of the skin to a low dose of UV-B radiation increases luminescence in the exposed areas. In ocular experiments, LPS- and TNF-alpha injected NF-kappaB-luciferase transgenic mice exhibit a 20-40-fold increase in lens NF-kappaB activity, similar to other LPS- and TNF-alpha-responsive organs. Peak NF-kappaB activity occurs 6h after injection of TNF-alpha and 12h after injection of LPS. Peak activities occur, respectively, 3 and 6h later than that in other tissues. Mice exposed to 360J/m(2) of UV-B exhibit a 16-fold increase in NF-kappaB activity 6h after exposure, characteristically similar to TNF-alpha-exposed mice. Thus, in NF-kappaB-luciferase transgenic mice, NF-kappaB activity also occurs in lens epithelial tissue and is activated when the intact mouse is exposed to classical stressors. Furthermore, as revealed by real-time non-invasive imaging, induction of chronic inflammation resembling rheumatoid arthritis produces strong NF-kappaB activity in the affected joints. Finally, we have used the model to demonstrate NF-kappaB regulation by manipulating the Vitamin A status in mice. NF-kappaB activity is elevated in mice fed a Vitamin A deficient (VAD) diet, and suppressed by surplus doses of retinoic acid (RA). We thus demonstrate the development and use of a versatile model for monitoring NF-kappaB activation both in tissue homogenates and in intact animals after the use of classical activators, during disease progression and after dietary intervention.
Publication Types:
Review
PMID: 15225593 [PubMed - indexed for MEDLINE]
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Post by Max on Sept 6, 2005 15:09:00 GMT -5
Biochem Biophys Res Commun. 2000 Feb 16;268(2):255-61. Related Articles, Links
Evidence for translational repression of the SOCS-1 major open reading frame by an upstream open reading frame.
Schluter G, Boinska D, Nieman-Seyde SC.
Institute of Human Genetics, University of Gottingen, Heinrich-Duker-Weg 12, Gottingen, 37073, Germany. gschlue@gwdg.de
The suppressor of cytokine signalling 1 protein (SOCS-1) belongs to a novel family of cytokine inducible factors which function as inhibitors of the JAK/STAT pathway. While SOCS-1 previously has been described as a single-exon gene, here we present evidence for an additional 5' exon, separated by a 509 bp intron from exon 2. Exon 1 and part of exon 2 contain an open reading frame of 115 nt, ending one nucleotide upstream of the major reading frame. Using SOCS-1-promoter/luciferase constructs, we investigated which sequences are involved in the regulation of SOCS-1 expression. Serial promoter deletion clones indicate the localization and functionality of SP1, interferon-stimulated responsive elements (ISRE), and interferon-gamma-activated sites (GAS) promoter elements in the SOCS-1 5' flanking region. We present evidence that the upstream open reading frame (uORF) represses the translation of the downstream major open reading frame (mORF). Mutating the start codon of the uORF relieves this repression. Our data indicate that expression of the SOCS-1 protein is repressed on translational level by a mechanism, which bears similarities to that postulated for genes like retinoic acid receptor beta2 (RARbeta2), S-adenosylmethionine-decarboxylase (AdoMetDC), Bcl-2, and others. Copyright 2000 Academic Press.
PMID: 10679190 [PubMed - indexed for MEDLINE]
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Post by Max on Sept 6, 2005 15:10:23 GMT -5
Proc Natl Acad Sci U S A. 2004 Jul 13;101(28):10422-7. Epub 2004 Jul 6. Related Articles, Links
Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse.
Ueki K, Kondo T, Tseng YH, Kahn CR.
Research Division, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Insulin resistance, obesity, diabetes, dyslipidemia, and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism is poorly understood. Here we show that overexpression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 in liver causes insulin resistance and an increase in the key regulator of fatty acid synthesis in liver, sterol regulatory element-binding protein (SREBP)-1c. Conversely, inhibition of SOCS-1 and -3 in obese diabetic mice improves insulin sensitivity, normalizes the increased expression of SREBP-1c, and dramatically ameliorates hepatic steatosis and hypertriglyceridemia. In obese animals, increased SOCS proteins enhance SREBP-1c expression by antagonizing STAT3-mediated inhibition of SREBP-1c promoter activity. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating insulin signaling and cytokine signaling.
PMID: 15240880 [PubMed - indexed for MEDLINE]
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Post by dghjdjdj on Sept 7, 2018 19:28:19 GMT -5
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