Turner, J. J. O., Foxwell, K. M., Kanji, R., Brenner, C., Wood, S., Foxwell, B. M. J. and Feldmann, M. (2010) Investigation of nuclear factor-κB inhibitors and interleukin-10 as regulators of inflammatory signalling in human adipocytes. Clinical and Experimental Immunology, 162 (3). pp. 487-493. ISSN 1365-2249
Full text not available from this repository. (Request a copy)Abstract
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.
Item Type: | Article |
---|---|
Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
UEA Research Groups: | Faculty of Medicine and Health Sciences > Research Groups > Norwich Clinical Trials Unit |
Depositing User: | Rhiannon Harvey |
Date Deposited: | 20 Apr 2011 12:56 |
Last Modified: | 12 Mar 2024 10:30 |
URI: | https://ueaeprints.uea.ac.uk/id/eprint/29734 |
DOI: | 10.1111/j.1365-2249.2010.04260.x |
Actions (login required)
![]() |
View Item |