Induction of TLR tolerance in human macrophages by adiponectin: does LPS play a role?
Obesity is regarded as a pro-inflammatory state. It is associated with low circulating levels of the adipokine, adiponectin, which is considered to be an anti-inflammatory. However, adiponectin knockout mice do not consistently demonstrate pro-inflammatory phenotypes, suggesting more complexity in the in vivo immunomodulatory effects of adiponectin than originally anticipated. Moreover, adiponectin exerts pro-inflammatory effects in some experimental systems. This contradiction has been resolved by hypothesizing that adiponectin induces tolerance to inflammatory stimuli, notably Toll-like receptor (TLR) ligands. We noticed that this effect resembled lipopolysaccharide (LPS) tolerance and therefore tested adiponectin from a variety of sources for LPS contamination. All adiponectin tested carried low levels of LPS in the range of 1-30 pg/microg of adiponectin, sufficient to produce final LPS concentrations in the pg/ml range under experimental conditions. We found that induction of tolerance to TLR ligands by adiponectin in human monocyte-derived macrophages could be reproduced by such LPS concentrations. Moreover, the LPS antagonist, polymixin B, substantially inhibited induction of tolerance by adiponectin. Furthermore, polymixin B and a naturally occurring antagonist LPS were able to partially attenuate induction of tumour necrosis factor-alpha and interleukin-6 in human monocyte-derived macrophages by adiponectin. Polymixin B also inhibited nuclear factor-kappaB and mitogen-activated protein kinase signalling elicited by adiponectin. We therefore propose that some of adiponectin's immunomodulatory effects, in particular, its TLR-tolerising actions in human monocyte-derived macrophages, may be confounded by induction of tolerance by contaminating LPS.
Turner
J J O
JJ
Kennedy Institute of Rheumatology, Imperial College, London, UK. jeremy.turner@imperial.ac.uk
Smolinska
M J
MJ
Sacre
S M
SM
Foxwell
B M J
BM
D052242:Adiponectin / Q000276:immunology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004340:Drug Contamination; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007108:Immune Tolerance; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D011112:Polymyxin B / Q000494:pharmacology; D011994:Recombinant Proteins / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
D052242:Adiponectin; D000900:Anti-Bacterial Agents; D016207:Cytokines; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D011112:Polymyxin B