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. However, IL-15 and IL-2 differ in their controls of expression and secretion, their range of target cells and their functional activities. These dissimilarities may include differential effects on apoptosis. For example, IL-2 induces or inhibits T-cell apoptosis in vitro, depending on T-cell activation, whereas IL-15 inhibits cytokine deprivation-induced apoptosis in activated T cells. Studying whether and how IL-15 modulates distinct apoptosis pathways, 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.
Bulfone-Paus
S
S
Institute of Immunology, Benjamin Franklin Medical Center, Free University Berlin, Germany. bulfone@zedat.fu-berlin.de
Ungureanu
D
D
Pohl
T
T
Lindner
G
G
Paus
R
R
Rückert
R
R
Krause
H
H
Kunzendorf
U
U
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology / Q000502:physiology; D002478:Cells, Cultured; D053938:DNA Fragmentation; D003907:Dexamethasone / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007075:Immunoglobulin M / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D051379:Mice; D014066:Palatine Tonsil; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D014158:Transcription, Genetic; D019014:fas Receptor / Q000276:immunology / Q000502:physiology
D017252:CD3 Complex; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D019409:Interleukin-15; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D003907:Dexamethasone