Ogston N C, Karastergiou K, Hosseinzadeh-Attar M J, Bhome R, Madani R, Stables M, Gilroy D, Flachs P, Hensler M, Kopecky J, Mohamed-Ali V
Adipokines and Metabolism Research Group, University College London, London, UK.
Int J Obes (Lond). 2008 Dec;32(12):1807-15. doi: 10.1038/ijo.2008.190. Epub 2008 Nov 4.
Chronically elevated interleukin-6 (IL-6) is implicated in obesity-associated pathologies, where a proportion of this cytokine is derived from adipose tissue. Proinflammatory prostaglandins, which regulate this cytokine elsewhere, are also produced by this tissue.
To investigate whether constitutively active cyclooxygenase (COX)/prostaglandin (PG) pathway in white adipose tissue (WAT) is responsible for basal IL-6 production.
The effect of acetylsalicylic acid (ASA), an inhibitor of COX, on IL-6 was assessed in human subjects and mice. COX, downstream PG synthase (PGS) activity and PG receptor signalling were determined in subcutaneous (SC), gonadal (GN) WAT and adipocytes.
In obese humans, low-dose ASA (150 mg day(-1) for 10 days) inhibited systemic IL-6 and reduced IL-6 release from SC WAT ex vivo (0.2 mM). Similarly, in mice, ASA (0.2 and 2.0 mg kg(-1)) suppressed SC WAT 6-keto-PGF(1alpha) (a stable metabolite of prostacyclin) and IL-6 release. Although both COX isoforms are comparably expressed, prostacyclin synthase expression is higher in GN WAT, with levels of activity correlating directly with IL-6. Both ASA (5 mM) and NS-398 (COX-2 selective inhibitor <or=1 microM), but not SC-560 (COX-1 selective inhibitor <or=1 microM), attenuated IL-6 release from murine WAT in vitro and abolished its depot differences. Prostacyclin receptor (IP) and, to a lesser extent, PGE(2) (EP2 and EP4) receptor agonists elevated the release of IL-6 from adipocytes.
In adipose tissue, constitutive COX-2-coupled prostacyclin triggers the release of basal IL-6, which in obese subjects is significantly dampened by ASA ingestion, thus offering a novel, modifiable pathway to regulate the potentially pathological component of this cytokine.
白细胞介素-6（IL-6）长期升高与肥胖相关疾病有关，其中一部分这种细胞因子来源于脂肪组织。在其他地方调节这种细胞因子的促炎前列腺素也由该组织产生。
研究白色脂肪组织（WAT）中组成型活性环氧化酶（COX）/前列腺素（PG）途径是否负责基础IL-6的产生。
在人类受试者和小鼠中评估COX抑制剂乙酰水杨酸（ASA）对IL-6的影响。在皮下（SC）、性腺（GN）白色脂肪组织和脂肪细胞中测定COX、下游PG合酶（PGS）活性和PG受体信号传导。
在肥胖人类中，低剂量ASA（150毫克/天，持续10天）抑制全身IL-6并降低离体SC白色脂肪组织中IL-6的释放（0.2毫摩尔）。同样，在小鼠中，ASA（0.2和2.0毫克/千克）抑制SC白色脂肪组织中6-酮-PGF（1α）（前列环素的稳定代谢物）和IL-6的释放。虽然两种COX同工型表达相当，但前列环素合酶在GN白色脂肪组织中的表达较高，活性水平与IL-6直接相关。ASA（5毫摩尔）和NS-398（COX-2选择性抑制剂≤1微摩尔），但不是SC-560（COX-1选择性抑制剂≤1微摩尔），在体外减弱了小鼠白色脂肪组织中IL-6的释放并消除了其储存差异。前列环素受体（IP）以及在较小程度上PGE（2）（EP2和EP4）受体激动剂提高了脂肪细胞中IL-6的释放。
在脂肪组织中，组成型COX-2偶联的前列环素触发基础IL-6的释放，在肥胖受试者中，ASA摄入可显著抑制这种释放，从而提供了一种新的、可调节的途径来调节这种细胞因子的潜在病理成分。
