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-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.
Publication types
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Research Support, Non-U.S. Gov't
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Retracted Publication
MeSH terms
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Amino Acid Sequence
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Animals
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Apoptosis / drug effects*
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Apoptosis / physiology
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Binding Sites
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / physiology
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Flow Cytometry
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Interleukin-15 / pharmacology*
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L Cells
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Macromolecular Substances
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Mice
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Proteins / chemistry
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Proteins / physiology*
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Receptors, Interleukin-15
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Receptors, Interleukin-2 / chemistry
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Receptors, Interleukin-2 / genetics
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Receptors, Interleukin-2 / physiology*
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Receptors, Tumor Necrosis Factor / physiology
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Recombinant Proteins / biosynthesis
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Reverse Transcriptase Polymerase Chain Reaction
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Sequence Alignment
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Sequence Homology, Amino Acid
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TNF Receptor-Associated Factor 2
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Transfection
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Tumor Necrosis Factor-alpha / antagonists & inhibitors
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Tumor Necrosis Factor-alpha / pharmacology*
Substances
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Il15ra protein, mouse
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Interleukin-15
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Macromolecular Substances
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Proteins
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Receptors, Interleukin-15
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Receptors, Interleukin-2
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Receptors, Tumor Necrosis Factor
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Recombinant Proteins
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TNF Receptor-Associated Factor 2
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Tumor Necrosis Factor-alpha