Mechanism of cytokine-induced cellular senescence

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Normal cells undergo senescence in response to various stresses, such as DNA damage and certain cytokines. One such cytokine, interleukin-6 (IL-6), a multifunctional cytokine, can act on multiple lineages of cells combination with soluble IL-6 receptor α (sIL-6Rα) to induce cell proliferation, differentiation and even promotion of tumorigenesis. We studied the molecular mechanisms by which IL-6 and sIL-6Rα cause premature senescence using primary human fibroblasts. Stimulation of fibroblasts cells with IL-6/sIL-6Rα sequentially caused generation of reactive oxygen species (ROS) as early as day 1, followed by DNA damage, p53 accumulation, and finally senescence. STAT3 was required for the early and late events leading to senescence, including the early-phase increase of ROS and senescence-associated secretary phenotype occurring 4 days after IL-6/sIL-6Ra stimulation. Interestingly, Insulin-like growth factor-binding protein 5 (IGFBP-5) secreted into the supernatants was identified as the STAT3-downstream molecule responsible for the IL-6/STAT3-induced ROS generation and premature senescence. IGFBP-5 was consistently expressed from the initial phase through the entire senescence process, the profile being quite different from that of senescence-associated secretary phenotype. Thus, IL-6/sIL-6R? forms a senescence-inducing circuit involving the STAT3?IGFBP5 axis as a key triggering and reinforcing component.