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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.

Original publication

DOI

10.1111/j.1365-2249.2010.04260.x

Type

Journal article

Journal

Clin Exp Immunol

Publication Date

12/2010

Volume

162

Pages

487 - 493

Keywords

Adipocytes, Amides, Cells, Cultured, Chemokine CCL2, Humans, Inflammation, Interleukin-10, Interleukin-6, NF-kappa B, Obesity, Receptors, Interleukin-10, STAT3 Transcription Factor, Thiophenes, Toll-Like Receptor 4, Transgenes