College of Pharmacy, Yeungnam University, Gyeongsan, Republic of Korea.
Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Republic of Korea.
Arch Pharm Res. 2022 Jan;45(1):38-50. doi: 10.1007/s12272-021-01364-0. Epub 2021 Nov 19.
Adiponectin, an adipose tissue-derived hormone, exhibits a modulatory effect on cell death/survival and possesses potent anti-inflammatory properties. However, the underlying molecular mechanisms remain elusive. Sestrin2, a stress-inducible metabolic protein, has shown cytoprotective and inflammation-modulatory effects under stressful conditions. In this study, we examined the role of sestrin2 signaling in the modulation of cell survival and inflammatory responses by globular adiponectin (gAcrp) in macrophages. We observed that gAcrp induced a significant increase in sestrin2 expression in both RAW 264.7 murine macrophages and primary murine macrophages. Notably, gAcrp treatment markedly increased expression of hypoxia inducible factor-1 α (HIF-1α) and gene silencing of HIF-1α blocked sestrin2 induction by gAcrp. In addition, pretreatment with a pharmacological inhibitor of ERK or PI3K abrogated both sestrin2 and HIF-1α expression by gAcrp, indicating that ERK/PI3K-mediated HIF-1α signaling pathway plays a critical role in sestrin2 induction by gAcrp. Furthermore, sestrin2 induction is implicated in autophagy activation, and knockdown of sestrin2 prevented enhanced cell viability by gAcrp. Moreover, gene silencing of sestrin2 caused restoration of gAcrp-induced expression of anti-inflammatory genes in a gene-selective manner. Taken together, these results indicate that sestrin2 induction critically contributes to cell survival and anti-inflammatory responses by gAcrp in macrophages.
脂联素是一种脂肪组织来源的激素，对细胞死亡/存活具有调节作用，并具有强大的抗炎特性。然而，其潜在的分子机制仍不清楚。Sestrin2 是一种应激诱导的代谢蛋白，在应激条件下表现出细胞保护和炎症调节作用。在本研究中，我们研究了 sestrin2 信号在球状脂联素 (gAcrp) 调节巨噬细胞中细胞存活和炎症反应中的作用。我们观察到 gAcrp 诱导 RAW 264.7 鼠巨噬细胞和原代鼠巨噬细胞中 sestrin2 表达显著增加。值得注意的是，gAcrp 处理显著增加了缺氧诱导因子-1α (HIF-1α) 的表达，并且 HIF-1α 的基因沉默阻断了 gAcrp 诱导 sestrin2 的表达。此外，ERK 或 PI3K 的药理学抑制剂预处理阻断了 gAcrp 对 sestrin2 和 HIF-1α 的表达，表明 ERK/PI3K 介导的 HIF-1α 信号通路在 gAcrp 诱导 sestrin2 中起关键作用。此外， sestrin2 诱导与自噬激活有关，sestrin2 的敲低阻止了 gAcrp 增强细胞活力。此外，sestrin2 的基因沉默以基因选择性的方式恢复了 gAcrp 诱导的抗炎基因的表达。总之，这些结果表明 sestrin2 诱导在巨噬细胞中对 gAcrp 的细胞存活和抗炎反应具有重要作用。
