Son Yonghae, Kim Bo-Young, Kim Miran, Kim Jaesung, Kwon Ryuk Jun, Kim Koanhoi
Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Korea.
Family Medicine Clinic and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Korea.
Immune Netw. 2023 Oct 19;23(5):e40. doi: 10.4110/in.2023.23.e40. eCollection 2023 Oct.
Glucocorticoids suppress the vascular inflammation that occurs under hypercholesterolemia, as demonstrated in an animal model fed a high-cholesterol diet. However, the molecular mechanisms underlying these beneficial effects remain poorly understood. Because cholesterol is oxidized to form cholesterol oxides (oxysterols) that are capable of inducing inflammation, we investigated whether glucocorticoids affect the immune responses evoked by 7α-hydroxycholesterol (7αOHChol). The treatment of human THP-1 monocytic cells with dexamethasone (Dex) and prednisolone (Pdn) downregulated the expression of pattern recognition receptors (PRRs), such as TLR6 and CD14, and diminished 7αOHChol-enhanced response to FSL-1, a TLR2/6 ligand, and lipopolysaccharide, which interacts with CD14 to initiate immune responses, as determined by the reduced secretion of IL-23 and CCL2, respectively. Glucocorticoids weakened the 7αOHChol-induced production of CCL2 and CCR5 ligands, which was accompanied by decreased migration of monocytic cells and CCR5-expressing Jurkat T cells. Treatment with Dex or Pdn also reduced the phosphorylation of the Akt-1 Src, ERK1/2, and p65 subunits. These results indicate that both Dex and Pdn impair the expression of PRRs and their downstream products, chemokine production, and phosphorylation of signaling molecules. Collectively, glucocorticoids suppress the innate immune response and activation of monocytic cells to an inflammatory phenotype enhanced or induced by 7αOHChol, which may contribute to the anti-inflammatory effects in hypercholesterolemic conditions.
糖皮质激素可抑制高胆固醇血症时发生的血管炎症，这在喂食高胆固醇饮食的动物模型中得到了证实。然而，这些有益作用背后的分子机制仍知之甚少。由于胆固醇被氧化形成能够诱导炎症的氧化胆固醇（氧甾醇），我们研究了糖皮质激素是否会影响由7α-羟基胆固醇（7αOHChol）引发的免疫反应。用地塞米松（Dex）和泼尼松龙（Pdn）处理人THP-1单核细胞可下调模式识别受体（PRR）如TLR6和CD14的表达，并减弱7αOHChol增强的对FSL-1（一种TLR2/6配体）和脂多糖的反应，脂多糖与CD14相互作用以启动免疫反应，这分别通过IL-23和CCL2分泌减少来确定。糖皮质激素减弱了7αOHChol诱导的CCL2和CCR5配体的产生，这伴随着单核细胞和表达CCR5的Jurkat T细胞迁移的减少。用Dex或Pdn处理也降低了Akt-1 Src、ERK1/2和p65亚基的磷酸化。这些结果表明，Dex和Pdn均损害PRR及其下游产物的表达、趋化因子的产生以及信号分子的磷酸化。总的来说，糖皮质激素抑制先天免疫反应以及单核细胞向由7αOHChol增强或诱导的炎症表型的激活，这可能有助于在高胆固醇血症情况下发挥抗炎作用。
