Department of Pharmacology and Toxicology, Faculty of Health, Medicine, and Life Sciences, Maastricht University, 6200 MD Maastricht, The Netherlands.
Faculty of Science and Engineering, Campus Venlo, Maastricht University, 5911 AA Venlo, The Netherlands.
Nutrients. 2020 Feb 10;12(2):441. doi: 10.3390/nu12020441.
Glucocorticoids are very effective anti-inflammatory drugs and widely used for inflammatory bowel disease (IBD) patients. However, approximately 20% of IBD patients do not respond to glucocorticoids and the reason for this is largely unknown. Dietary advanced glycation endproducts (AGEs) are formed via the Maillard reaction during the thermal processing of food products and can induce a pro-inflammatory reaction in human cells. To investigate whether this pro-inflammatory response could be mitigated by glucocorticoids, human macrophage-like cells were exposed to both LPS and AGEs to induce interleukin-8 (IL8) secretion. This pro-inflammatory response was then modulated by adding pharmacological compounds interfering in different steps of the anti-inflammatory mechanism of glucocorticoids: rapamycin, quercetin, and theophylline. Additionally, intracellular reactive oxygen species (ROS) were measured and the glucocorticoid receptor phosphorylation state was assessed. The results show that AGEs induced glucocorticoid resistance, which could be mitigated by quercetin and rapamycin. No change in the phosphorylation state of the glucocorticoid receptor was observed. Additionally, intracellular ROS formation was induced by AGEs, which was mitigated by quercetin. This suggests that AGE-induced ROS is an underlying mechanism to AGE-induced glucocorticoid resistance. This study shows for the first time the phenomenon of dietary AGE-induced glucocorticoid resistance due to the formation of ROS. Our findings indicate that food products with a high inflammatory potential can induce glucocorticoid resistance; these results may be of great importance to IBD patients suffering from glucocorticoid resistance.
糖皮质激素是一种非常有效的抗炎药物，广泛用于炎症性肠病（IBD）患者。然而，大约 20%的 IBD 患者对糖皮质激素没有反应，而其原因在很大程度上尚不清楚。膳食晚期糖基化终产物（AGEs）是在食品加工过程中的美拉德反应中形成的，可以在人类细胞中诱导炎症反应。为了研究这种促炎反应是否可以被糖皮质激素减轻，人类巨噬细胞样细胞被暴露于 LPS 和 AGEs 以诱导白细胞介素-8（IL8）的分泌。然后，通过添加药理学化合物来调节这种促炎反应，这些化合物干扰了糖皮质激素抗炎机制的不同步骤：雷帕霉素、槲皮素和茶碱。此外，还测量了细胞内活性氧（ROS）的形成，并评估了糖皮质激素受体的磷酸化状态。结果表明，AGEs 诱导了糖皮质激素抵抗，而槲皮素和雷帕霉素可以减轻这种抵抗。没有观察到糖皮质激素受体磷酸化状态的变化。此外，AGEs 诱导了细胞内 ROS 的形成，而槲皮素减轻了这种形成。这表明 AGE 诱导的 ROS 是 AGE 诱导的糖皮质激素抵抗的潜在机制。这项研究首次表明了由于 ROS 形成而导致的膳食 AGE 诱导的糖皮质激素抵抗现象。我们的研究结果表明，具有高炎症潜力的食物产品可能会诱导糖皮质激素抵抗；这些结果对于患有糖皮质激素抵抗的 IBD 患者可能非常重要。
