TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion
| Autor: | Tamara Tchkonia, Jaume Alijotas-Reig, Simó Schwartz, James L. Kirkland, Renuka Kandhaya-Pillai, Francesc Miró-Mur |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
STAT3 Transcription Factor 0301 basic medicine Senescence Aging senescence Time Factors medicine.medical_treatment interferon response genes 03 medical and health sciences 0302 clinical medicine JAK/STAT pathway Human Umbilical Vein Endothelial Cells medicine Humans STAT1 Autocrine signalling Cells Cultured Cellular Senescence Cyclin-Dependent Kinase Inhibitor p16 Cell Proliferation Janus Kinases Feedback Physiological biology DNA-damage Tumor Necrosis Factor-alpha Chemistry JAK-STAT signaling pathway Cell Cycle Checkpoints Cell Biology beta-Galactosidase Cell biology STAT1 Transcription Factor 030104 developmental biology Cytokine Gene Expression Regulation inflammation 030220 oncology & carcinogenesis Interferon Regulatory Factors Immunology biology.protein Cytokines Cytokine secretion Reactive Oxygen Species Janus kinase Research Paper DNA Damage Signal Transduction Interferon regulatory factors |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| DOI: | 10.18632/aging.101328 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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