Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway

Interleukin-11 (IL-11) reduces injury both in vivo and in vitro, but the me chanisms are unknown. Stimulation of serum- and growth factor-deprived HUVE C with IL-11 increased survivin mRNA and protein expression levels in a dos e-dependent manner, with maximal induction at 50 to 100 ng/ml of IL-11. Sur vivin mRNA expression peaked after 3 to 6 hours of IL-11 treatment and decr eased by 24 hours. Survivin protein expression was maximal at 6 hours of tr eatment and remained elevated through 24 hours. Survivin induction may be m ediated by activation of protein kinase B/Akt, but IL-11 failed to activate this pathway in HUVEC. IL-11 did activate signal transducer and activator of transcription (STAT)-3 and IL-11 failed to induce survivin expression in HUVEC transduced with a dominant-negative STAT3 mutant, whereas control-tr ansduced HUVEC responded normally. An IL-11 transgene caused increased surv ivin mRNA expression in mice compared with control littermates. Intradermal injection of IL-11 (500 ng) into human skin xenografts on immunodeficient mice up-regulated survivin protein in microvascular endothelium and epithel ial keratinocytes. We conclude that IL-11 induces expression of survivin, a n antiapoptotic protein, in vitro and in vivo, and identify STATE as a crit ical mediator of this response.