Death deflected: IL-15 inhibits TNF-alpha-mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL-15Ralpha chain.
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-15Ralpha chain signaling. The intracellular tail of IL-15Ralpha shows sequence homologies to the TRAF2 binding motifs of CD30 and CD40. Most important, binding of IL-15 to IL-15Ralpha successfully competes with the TNFR1 complex for TRAF2 binding, which may impede assembly of key adaptor proteins to the TNFR1 complex, and induces IkappaBalpha phosphorylation. Thus, IL-15Ralpha chain stimulation is a powerful deflector of cell death very early in the apoptosis signaling cascade, while TNF-alpha and IL-15 surface as major opponents in apoptosis control.
Bulfone-Paus
S
S
Institute of Immunology, Department of Urology, Department of Pathology, University Hospital Benjamin Franklin, Free University, Berlin, Germany. bulfone@zedat.fu-berlin.de
Bulanova
E
E
Pohl
T
T
Budagian
V
V
Durkop
H
H
Ruckert
R
R
Kunzendorf
U
U
Paus
R
R
Krause
H
H
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001665:Binding Sites; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D005434:Flow Cytometry; D019409:Interleukin-15 / Q000494:pharmacology*; D007739:L Cells; D046911:Macromolecular Substances; D051379:Mice; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D011994:Recombinant Proteins / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D047992:TNF Receptor-Associated Factor 2; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
C508025:Il15ra protein, mouse; D019409:Interleukin-15; D046911:Macromolecular Substances; D011506:Proteins; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha