Investigation of nuclear factor-κB inhibitors and interleukin-10 as regulators of inflammatory signalling in human adipocytes.
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.
Turner
J J O
JJ
Kennedy Institute of Rheumatology, Charing Cross Hospital, London, UK. jeremy.turner@nnuh.nhs.uk
Foxwell
K M
KM
Kanji
R
R
Brenner
C
C
Wood
S
S
Foxwell
B M J
BM
Feldmann
M
M
D017667:Adipocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D000577:Amides / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D009765:Obesity / Q000188:drug therapy / Q000276:immunology*; D053701:Receptors, Interleukin-10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism; D019076:Transgenes / Q000235:genetics
D000577:Amides; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D015850:Interleukin-6; D016328:NF-kappa B; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C495345:TLR4 protein, human; D013876:Thiophenes; D051197:Toll-Like Receptor 4; D016753:Interleukin-10; C499326:2-((aminocarbonyl)amino)-5-(4-fluorophenyl)-3-thiophenecarboxamide