Zhang Kehong, Jordan Paul Mike, Pace Simona, Hofstetter Robert K, Werner Markus, Chen Xinchun, Werz Oliver
Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, D-07743, Germany.
Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, Shenzhen University School of Medicine, Shenzhen, 518000, People's Republic of China.
J Inflamm Res. 2022 Jun 2;15:3285-3304. doi: 10.2147/JIR.S356964. eCollection 2022.
Celastrol (CS) is a major active ingredient of the Chinese/Asian herb that is frequently used as phytomedicine to treat inflammation and autoimmune diseases. We showed before that short-term exposure to CS (1 µM) favorably impacts the biosynthesis of inflammation-related lipid mediators (LM) in human polarized macrophages by modulating the activities of different lipoxygenases (LOXs). However, whether CS regulates the expression of LOXs and other related LM-biosynthetic enzymes during macrophage polarization is unknown. Here, we investigated how CS affects LM-biosynthetic enzyme expression on the protein level and studied concomitant LM signature profiles during polarization of human monocyte-derived macrophages (MDM) towards M1- and M2-like phenotypes.
We used LM metabololipidomics to study the long-term effects of CS on LM profile signatures after manipulation of human monocyte-derived macrophages (MDM) during polarization. Exposure of MDM to low concentrations of CS (ie, 0.2 µM) during polarization to an inflammatory M1 phenotype potently suppressed the formation of pro-inflammatory cyclooxygenase (COX)- and 5-LOX-derived LM, especially prostaglandin (PG)E. Notably, gene and enzyme expression of COX-2 and microsomal PGE synthase (mPGES)-1 as well as M1 markers were strongly decreased by CS during M1-MDM polarization, along with impaired activation of nuclear factor-κB and p38 mitogen-activated protein kinase. During IL-4-induced M2 polarization, CS decreased the capacity of the resulting M2-MDM to generate pro-inflammatory COX and 5-LOX products as well but it also reduced the formation of 12/15-LOX products and specialized pro-resolving mediators, without affecting the levels of liberated fatty acid substrates.
Depending on the timing and concentration, CS not only favorably affects LOX activities in macrophages but also the expression of LM-biosynthetic enzymes during macrophage polarization connected to changes of inflammation-related LM which might be of relevance for potential application of CS to treat inflammatory disorders.
雷公藤红素（CS）是一种常见于中国/亚洲草药中的主要活性成分，常被用作植物药来治疗炎症和自身免疫性疾病。我们之前的研究表明，短期暴露于CS（1 μM）可通过调节不同脂氧合酶（LOXs）的活性，对人极化巨噬细胞中炎症相关脂质介质（LM）的生物合成产生有利影响。然而，CS在巨噬细胞极化过程中是否调节LOXs及其他相关LM生物合成酶的表达尚不清楚。在此，我们研究了CS如何在蛋白质水平上影响LM生物合成酶的表达，并研究了人单核细胞衍生巨噬细胞（MDM）向M1和M2样表型极化过程中伴随的LM特征谱。
我们使用LM代谢脂质组学研究了CS在人单核细胞衍生巨噬细胞（MDM）极化过程中对LM谱特征的长期影响。在极化至炎症性M1表型的过程中，将MDM暴露于低浓度的CS（即0.2 μM）可有效抑制促炎环氧化酶（COX）和5-脂氧合酶衍生的LM的形成，尤其是前列腺素（PG）E。值得注意的是，在M1-MDM极化过程中，CS可使COX-2和微粒体PGE合酶（mPGES）-1的基因和酶表达以及M1标志物显著降低，同时核因子-κB和p38丝裂原活化蛋白激酶的激活受损。在白细胞介素-4诱导的M2极化过程中，CS也降低了所得M2-MDM产生促炎COX和5-脂氧合酶产物的能力，但同时也减少了12/15-脂氧合酶产物和特殊促消退介质的形成，而不影响游离脂肪酸底物的水平。
根据时间和浓度的不同，CS不仅对巨噬细胞中的LOX活性有有利影响，而且在巨噬细胞极化过程中对LM生物合成酶的表达也有影响，这与炎症相关LM的变化有关，这可能与CS在治疗炎症性疾病中的潜在应用有关。
