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-1 alpha/beta, 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.