TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion.
TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion.
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DOI：
10.18632/aging.101328
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发表时间：
2017-11-22
期刊：
影响因子：
--
通讯作者：
Schwartz S
中科院分区：
文献类型：
--
作者：
Kandhaya-Pillai R;Miro-Mur F;Alijotas-Reig J;Tchkonia T;Kirkland JL;Schwartz S
细胞衰老是一种细胞命运程序，其需要响应于损伤信号的基本上不可逆的增殖停滞。肿瘤坏死因子-α（TNFα）是由某些类型的衰老细胞分泌的一种重要的促炎细胞因子，可诱导小鼠和人细胞的衰老。然而，将TNFα相关炎症与衰老联系起来的下游信号通路尚未完全表征。以人脐静脉内皮细胞（HUVECs）为模型，我们发现TNFα可诱导永久性生长停滞，并增加p21 CIP 1、p16 INK 4A和SA-β-gal的表达，同时伴有持续性DNA损伤和ROS产生。通过基因表达谱分析，我们确定了炎症和JAK/STAT通路在TNFα介导的衰老中的关键参与。我们发现，TNFα激活STAT依赖性自分泌环，维持细胞因子分泌和干扰素特征以锁定细胞衰老。此外，我们还发现，在TNFα诱导的衰老过程中，STAT 1/3的激活是细胞因子和ROS产生所必需的。然而，抑制STAT 1/3并不能使细胞免于增殖停滞，而是抑制了细胞周期调控基因并改变了TNFα诱导的衰老。我们的研究结果表明，通过STAT途径维持细胞因子的产生的正反馈机制，并揭示了JAK/STAT在TNFα介导的衰老中的相互调节作用。
Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence. Furthermore, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from proliferative arrest, but rather suppressed cell cycle regulatory genes and altered TNFα-induced senescence. Our findings suggest a positive feedback mechanism via the STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence.
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影响因子：
13.6
作者：
Freund A;Orjalo AV;Desprez PY;Campisi J
通讯作者：
Campisi J
DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
通讯作者：
Passos JF
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
11.4
作者：
Goh, KC;Haque, SJ;Williams, BRG
通讯作者：
Williams, BRG
影响因子：
3.7
作者：
HAYFLICK, L;MOORHEAD, PS
通讯作者：
MOORHEAD, PS