IL-4/IL-13 signaling suppresses ABT-263-induced apoptosis in senescent human fibroblasts.

Abstract

Senescent cells, which have irreversibly arrested cell proliferation and a senescence-associated secretory phenotype, are characterized by the production of proinflammatory cytokines and growth factors. The selective clearance of senescent cells might have beneficial effects on physiological functions or aging-related diseases. Senolytic drugs, such as ABT-263, an inhibitor of BCL-2 family proteins, selectively kill senescent cells. In the present study, we investigated the effect of IL-4 and IL-13, which contribute to type 2 immunity and fibrosis, on ABT-263-induced apoptosis in senescent cells. Doxorubicin was used to induce senescence in TIG-1 cells, a normal diploid fibroblast line commonly used to study cellular senescence. Although ABT-263 selectively induced apoptosis in senescent TIG-1 cells at lower concentrations than were required to induce apoptosis in non-senescent cells, IL-4 and IL-13 suppressed ABT-263-induced apoptosis in senescent TIG-1 cells. Pharmacological experiments using inhibitors revealed that the suppressive effects of IL-4 and IL-13 involved the IL-4Rα/JAK/STAT6 signaling pathway. We found that IL-4 and IL-13 altered the expressions of molecules involved in extracellular matrix and cell adhesion, and induced phosphorylation of the downstream FAK/Akt/GSK3β signaling pathway. In addition, senescent TIG-1 cells treated with IL-4 and IL-13 showed increased glucose consumption, and the suppressive effect of IL-4 and IL-13 was partially abolished by inhibitors of the glucose metabolic pathway. Taken together, IL-4/IL-13 signaling had a suppressive effect on ABT-263-induced apoptosis in senescent human fibroblasts. These results suggest that a combination of senolytic drugs and inhibitors targeting IL-4/IL-13 signaling might be effective for aging-related diseases.