Turner J J O, Smolinska M J, Sacre S M, Foxwell B M J
Kennedy Institute of Rheumatology, Imperial College, London, UK.
Scand J Immunol. 2009 Apr;69(4):329-36. doi: 10.1111/j.1365-3083.2008.02224.x.
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.
肥胖被视为一种促炎状态。它与脂肪因子脂联素的循环水平降低有关，脂联素被认为具有抗炎作用。然而，脂联素基因敲除小鼠并不总是表现出促炎表型，这表明脂联素在体内的免疫调节作用比最初预期的更为复杂。此外，脂联素在一些实验系统中发挥促炎作用。通过假设脂联素诱导对炎症刺激（特别是Toll样受体（TLR）配体）的耐受性，这一矛盾得到了解决。我们注意到这种效应类似于脂多糖（LPS）耐受性，因此检测了来自各种来源的脂联素是否存在LPS污染。所有检测的脂联素都携带低水平的LPS，范围为每微克脂联素含1 - 30皮克，在实验条件下足以产生皮克/毫升范围内的最终LPS浓度。我们发现，脂联素在人单核细胞衍生的巨噬细胞中诱导对TLR配体的耐受性可由此类LPS浓度重现。此外，LPS拮抗剂多粘菌素B可显著抑制脂联素诱导的耐受性。此外，多粘菌素B和一种天然存在的拮抗剂LPS能够部分减弱脂联素在人单核细胞衍生的巨噬细胞中诱导肿瘤坏死因子-α和白细胞介素-6的作用。多粘菌素B还抑制脂联素引发的核因子-κB和丝裂原活化蛋白激酶信号传导。因此，我们提出脂联素的一些免疫调节作用，特别是其在人单核细胞衍生的巨噬细胞中对TLR的耐受作用，可能会被污染的LPS诱导的耐受性所混淆。
