The STAT3-IGFBP5 Axis is Critical for IL-6/gp130-induced Premature Senescence in Human Fibroblasts

Cells undergo senescence in response to various conditions, including telomere erosion, oncogene activation and multiple cytokines. One of these cytokines, interleukin-6 (IL‑6), not only functions in the immune system, but also promotes cellular senescence and cancer. Here we demonstrate that IL‑6 and the soluble IL‑6 receptor (sIL‑6R) induce premature senescence in normal human fibroblasts by establishing a senescence-inducing circuit involving the signal transducer and activator of transcription 3 (STAT3) and insulin-like growth factor-binding protein 5 (IGFBP5). Stimulating TIG3 fibroblast cells with IL‑6/sIL‑6R sequentially caused an increase in reactive oxygen species (ROS) as early as day 1, followed by the DNA damage response, p53 accumulation and, finally, senescence on days 8-10. We found that STAT3 was required for the events leading to senescence, including the initial early-phase ROS increase and the induction of IL‑1α/β, IL‑6 and CXCL8 mRNAs 4-5 d after IL‑6/sIL‑6R stimulation, suggesting that STAT3's role is indirect. We searched for STAT3-downstream molecule(s) responsible for the senescence-inducing activity in the supernatants of stimulated TIG3 and identified IGFBP5 as a major STAT3 mediator, because IGFBP5 was expressed from the early phase through the entire senescence process and was responsible for IL‑6/STAT3-induced ROS increase and premature senescence. Thus, IL‑6/sIL‑6R forms a senescence-inducing circuit involving the STAT3-IGFBP5 axis as a key triggering and reinforcing component.