下调和上调
细胞生物学
肿瘤坏死因子α
车站3
细胞因子
STAT蛋白
化学
信号转导
衰老
旁分泌信号
生物
内分泌学
免疫学
基因
生物化学
受体
作者
Sajjad Ashraf,J. Paul Santerre,Rita A. Kandel
标识
DOI:10.1096/fj.202002201r
摘要
Abstract Intervertebral disc degeneration is an irreversible process associated with accumulation of senescent nucleus pulposus (NP) cells. This study investigates the hypothesis that Tumor necrosis factor‐α (TNF‐α)–treated senescent NP cells propagate senescence of neighboring healthy cells via a paracrine effect that involves p‐Stat3 signaling and the cytokine interleukin‐6 (IL‐6). NP cells isolated from bovine caudal intervertebral disc (IVD) were treated with TNF‐α to induce senescence which was confirmed by demonstrating upregulation of senescence‐associated β‐galactosidase and p16. This was correlated with downregulation of NP‐associated markers, Aggrecan , Col2A1 , and Sox9 . Direct contact and non‐contact co‐culture of healthy and senescent cells showed that TNF‐α–treated cells increased the senescence in healthy cells via a paracrine effect. The senescent cells have a secretory phenotype as indicated by increased gene and protein levels of IL‐6. Phosphorylated Signal Transducer and Activator of Transcription 3 (pStat3) levels were also high in treated cells and appeared to upregulate IL‐6 as inhibition of Stat3 phosphorylation by StatticV downregulated IL‐6 mRNA expression in cells and protein levels in the culture media. All trans retinoic acid, an IL‐6 inhibitor, also decreased the secretion of IL‐6 and reduced the paracrine effect of senescent cells on healthy cells. Decreased pStat3 levels and inhibition of IL‐6 secretion did not fully restore NP gene expression of Col2A1 but importantly, appeared to cause senescent cells to undergo apoptosis and cell death. This study demonstrated the paracrine effect of senescent NP cells which involves Stat3 and IL‐6 and may explain why senescent NP cells accumulate in IVD with age. The role of pSTAT3 and IL‐6 in mediating NP senescence requires further study as it may be a novel strategy for modulating the senescent‐inducing effects of TNF‐α.
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