| Investigation of nuclear factor-κB inhibitors and interleukin-10 as regulators of inflammatory signalling in human adipocytes. | |
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MedLine Citation:
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PMID: 20846165 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The poor prognosis of obesity is now known to involve a proinflammatory state associated with elevated circulating levels of cytokines and with macrophage infiltration of adipose tissue. In particular, Toll-like receptor (TLR)-4-driven adipose inflammation has been implicated recently in obesity and the development of diabetes. Adipocytes are now recognized as an important source of cytokine and chemokine production, including interleukin (IL)-6 and monocyte chemotractant protein (MCP)-1, and this appears to be a key step in the development of the obesity-associated inflammatory state. Interventions targeted at adipocyte inflammation may therefore form novel therapies to treat or prevent medical complications of obesity. We set out to explore whether anti-inflammatory interventions which are effective in conventional immune cells would operate on primary human cultures of in-vitro differentiated adipocytes. IL-10 was ineffective against TLR-4-induced cytokine secretion due to lack of IL-10 receptor on human adipocytes, in contrast to the widely used murine 3T3-L1 adipocyte model, which is known to respond to IL-10. Adenoviral delivery of an IL-10 receptor construct to the cells restored IL-10 responsiveness as assessed by signal transducer and activator of transcription-3 (STAT-3) phosphorylation. However, the small molecule nuclear factor (NF)-κB inhibitors 2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA)-1 and carbobenzoxyl-Ile-Glu(O-t-butyl)-Ala-leucinal (PSI) as well as adenovirally delivered dominant negative inhibitor of IkappaB kinase 2 (IKK2) and wild-type IκBα were effective inhibitors of TLR-4-driven IL-6 and MCP-1 induction. These data identify a central role for canonical NF-κB signalling in adipocyte cytokine induction and indicate that small molecule inhibitors of NF-κB may form the basis of future treatments for obesity-related conditions where adipocyte inflammatory signalling is implicated. |
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Authors:
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J J O Turner; K M Foxwell; R Kanji; C Brenner; S Wood; B M J Foxwell; M Feldmann |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-15 |
Journal Detail:
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Title: Clinical and experimental immunology Volume: 162 ISSN: 1365-2249 ISO Abbreviation: Clin. Exp. Immunol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-11-12 Completed Date: 2011-03-08 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 0057202 Medline TA: Clin Exp Immunol Country: England |
Other Details:
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Languages: eng Pagination: 487-93 Citation Subset: IM |
Copyright Information:
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© 2010 Authors. Clinical and Experimental Immunology © 2010 British Society for Immunology. |
Affiliation:
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Kennedy Institute of Rheumatology, Charing Cross Hospital, London, UK. jeremy.turner@nnuh.nhs.uk |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adipocytes
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drug effects,
immunology,
metabolism*,
pathology Amides / pharmacology Cells, Cultured Chemokine CCL2 / biosynthesis, genetics, secretion Humans Inflammation* Interleukin-10 / immunology, metabolism Interleukin-6 / biosynthesis, genetics, secretion NF-kappa B / antagonists & inhibitors, immunology, metabolism* Obesity / drug therapy, immunology* Receptors, Interleukin-10 / genetics, immunology, metabolism* STAT3 Transcription Factor / genetics, metabolism Thiophenes / pharmacology Toll-Like Receptor 4 / immunology, metabolism Transgenes / genetics |
| Grant Support | |
ID/Acronym/Agency:
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072643/Z/03/Z//Wellcome Trust; G7811974//Medical Research Council; //Arthritis Research UK |
| Chemical | |
Reg. No./Substance:
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0/2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide; 0/Amides; 0/CCL2 protein, human; 0/Chemokine CCL2; 0/Interleukin-6; 0/NF-kappa B; 0/Receptors, Interleukin-10; 0/STAT3 Transcription Factor; 0/TLR4 protein, human; 0/Thiophenes; 0/Toll-Like Receptor 4; 130068-27-8/Interleukin-10 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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