Death deflected: IL‐15 inhibits TNF‐α‐mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL‐15Rα chain

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Abstract
Interleukin-15 (IL-15) is a potent inhibitor of several apoptosis pathways. One prominent path toward apoptosis is the ligand-induced association of TNF receptor 1 (TNFR1) with death domain adaptor proteins. Studying if and how IL-15 blocks TNFR1-mediated apoptosis in a murine fibroblast cell line (L929), we show here that IL-15 blocks TNFR1-induced apoptosis via IL-15Rα chain signaling. The intracellular tail of IL-15Rα shows sequence homologies to the TRAF2 binding motifs of CD30 and CD40. Most important, binding of IL-15 to IL-15Rα successfully competes with the TNFR1 complex for TRAF2 binding, which may impede assembly of key adaptor proteins to the TNFR1 complex, and induces IκBα phosphorylation. Thus, IL-15Rα chain stimulation is a powerful deflector of cell death very early in the apoptosis signaling cascade, while TNF-α and IL-15 surface as major opponents in apoptosis control.—Bulfone-Paus, S., Bulanova, E., Pohl, T., Budagian, V., Dürkop, H., Rückert, R., Kunzendorf, U., Paus, R., Krause, H. Dea...