Abstract
Normal cells undergo senescence in response to telomere erosion, various stresses causing DNA damage, and certain cytokines. One such cytokine, interleukin-6 (IL-6), a multifunctional cytokine, can act on multiple lineages of cells together with soluble IL-6 receptor to induce cell proliferation, differentiation, and even promotion of tumorigenesis. We studied the molecular mechanisms by which IL-6 and soluble IL-6R (sIL-6R) cause premature senescence using primary human TIG3 fibroblasts. Stimulation of TIG3 cells with IL-6/sIL-6R sequentially caused generation of reactive oxygen species (ROS) as early as day 1, followed by DNA damage, p53 accumulation, and finally senescence on days 8–10. Signal transducer and activator of transcription 3 (STAT3) was required for the early and late events leading to senescence, including the early-phase increase of ROS and senescence-associated secretary phenotype (SASP) occurring 4–5 days after IL-6/sIL-6R stimulation. Interestingly, the STAT3 function was indirect, and insulin-like growth factor-binding protein 5 (IGFBP5) secreted into the supernatants was identified as the STAT3-downstream molecule responsible for the IL-6/STAT3-induced ROS generation and premature senescence. IGFBP5 was consistently expressed from the initial phase through the entire senescence process, the profile being quite different from that of SASP. Thus, IL-6/sIL-6R forms a senescence-inducing circuit involving the STAT3–IGFBP5 axis as a key triggering and reinforcing component.
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Acknowledgements
This work was supported in part by the Ministry of Education, Culture, Sports, Science, and Technology of Japan; the Japan Health Foundation and the Kampou Science Foundation. The authors gratefully acknowledge their appreciation to members of the Nakajima laboratory for helpful discussions, to Junko Kanbara for excellent technical assistance.
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Kojima, H., Kunimoto, H., Inoue, T., Nakajima, K. (2014). Interleukin-6 Induces Premature Senescence Involving Signal Transducer and Activator of Transcription 3 and Insulin-Like Growth Factor-Binding Protein 5. In: Hayat, M. (eds) Tumor Dormancy, Quiescence, and Senescence, Volume 2. Tumor Dormancy and Cellular Quiescence and Senescence, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7726-2_6
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DOI: https://doi.org/10.1007/978-94-007-7726-2_6
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