Interleukin-15 protects from lethal apoptosis in vivo

Interleukin-15 shares many biological activities with IL-2 and signals through the IL-2 receptor beta and gamma chains(1-3). However, IL-15 and IL-2 differ in their controls of expression and secretion, their range of target cells and their functional activities(3-7). These dissimilarities may include differential effects on apoptosis. For ex ample, IL-2 induces or inhibits T-cell apoptosis in vitro, depending on T-cell activation(8), whereas IL-15 inhibits cytokine deprivation-induced apoptosis in activated T cells(9). Studying whether and how IL-15 modulates distinct apoptosis pathways(10-12), we show here that apoptosis induced by anti-fas, anti-CD3, dexamethasone, and/or anti-IgM in activated human T and B cells in vitro is inhibited by IL-15 in a manner dependent on RNA synthesis. In vivo, anti-fas-induced lethal multisystem apoptosis in mice is suppressed by a novel IL-15-IgG2b fusion protein. Only IL-15, but not IL-2, completely protected from lethal hepatic failure. Thus, IL-15 is a potent, general inhibitor of apoptosis in vitro and in vivo with intriguing therapeutic potential.