Longifolioside A 通过阻断 LPS 刺激的 THP-1 巨噬细胞中的 PKCδ 活化来抑制 TLR4 介导的炎症反应,Cytokine

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Longifolioside A 通过阻断 LPS 刺激的 THP-1 巨噬细胞中的 PKCδ 活化来抑制 TLR4 介导的炎症反应
Cytokine ( IF 3.7 ) Pub Date : 2020-07-01 , DOI: 10.1016/j.cyto.2020.155116
Su Ui Lee ₁ , Eun Sol Oh ₂ , Hyung Won Ryu ₁ , Mun-Ock Kim ₁ , Myung-Ji Kang ₁ , Yu Na Song ₂ , Ro Woon Lee ₂ , Doo-Young Kim ₁ , Hyunju Ro ₃ , Sunin Jung ₁ , Sung-Tae Hong ₄ , Sei-Ryang Oh ₁

Affiliation

Longifolioside A 是一种从 Pseudolysimachion rotundum var. 中分离的环烯醚萜苷化合物。subintegrum，已用于传统草药治疗呼吸道炎症疾病。Logifolioside A 是一种有效的抗氧化剂；然而，其在炎症性疾病中的潜在药理作用机制尚不清楚。在这里，我们使用人 THP-1 巨噬细胞和稳定表达人 TLR4 蛋白 (293/HA-hTLR4) 的 HEK293 细胞研究了长叶糖苷 A 在脂多糖 (LPS) 刺激的 toll 样受体 4 (TLR4) 信号转导系统中的抑制作用。Longifolioside A 显着减少了 LPS 刺激的 THP-1 巨噬细胞中炎症细胞因子的释放，如白细胞介素 (IL)-6、-8 和肿瘤坏死因子 (TNF)-α。此外，longifolioside A 抑制炎症介质基因的表达，例如分别产生一氧化氮 (NO) 和前列腺素 E2 (PGE2) 的诱导型一氧化氮合酶 (iNOS) 和环氧合酶 (COX)-2。Longifolioside A 抑制 PKCδ、IRAK4、IKKα/β、IκBα 和丝裂原活化蛋白 (MAP) 激酶（ERK 1/2 和 JNK，但不是 p38）的磷酸化，从而使 NF-κB 和 AP-的核定位失活1，从而降低炎症反应基因的表达。值得注意的是，长叶糖苷 A 破坏了人 TLR4 和包含 TIR 结构域的接头蛋白 (TIRAP) 之间的相互作用，这是 TLR4 激活过程中的一个早期步骤，从而减少了 293/HA-hTLR4 细胞中 IL-8 的分泌。这种抑制作用与 TAK-242（一种 TLR4 抑制剂，或 resatorvid）相当。

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Longifolioside A inhibits TLR4-mediated inflammatory responses by blocking PKCδ activation in LPS-stimulated THP-1 macrophages

Longifolioside A is an iridoid glucoside compound isolated from Pseudolysimachion rotundum var. subintegrum, which has been used in traditional herbal medicines to treat respiratory inflammatory diseases. Logifolioside A is a potent antioxidant; however, its underlying pharmacological mechanisms of action in inflammatory diseases are unknown. Here, we investigated the inhibitory effects of longifolioside A in lipopolysaccharide (LPS)-stimulated toll-like receptor 4 (TLR4) signal transduction systems using human THP-1 macrophages and HEK293 cells stably expressing human TLR4 protein (293/HA-hTLR4). Longifolioside A significantly reduced the release of inflammatory cytokines such as interleukin (IL)-6, -8, and tumor necrosis factor (TNF)-α in LPS-stimulated THP-1 macrophages. Furthermore, longifolioside A inhibited the expression of inflammatory mediator genes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 that produce nitric oxide (NO) and prostaglandin E2 (PGE2), respectively. Longifolioside A suppressed the phosphorylation of PKCδ, IRAK4, IKKα/β, IκBα, and mitogen-activated protein (MAP) kinases (ERK 1/2 and JNK, but not p38), thereby inactivating the nuclear localization of NF-κB and AP-1, and thus decreasing the expression of inflammatory response genes. Notably, longifolioside A disrupted the interaction between human TLR4 and the TIR domain-containing adaptor protein (TIRAP), an early step during TLR4 activation, thereby reducing IL-8 secretion in 293/HA-hTLR4 cells. This inhibitory effect was comparable to that of TAK-242 (a TLR4 inhibitor, or resatorvid). Our results indicate that longifolioside A prevents inflammatory response by suppressing TLR4 activation required for NF-κB and AP-1 activation.

更新日期：2020-07-01

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