The IL-15R alpha chain signals through association with Syk in human B cells

J Immunol. 2001 Dec 1;167(11):6292-302. doi: 10.4049/jimmunol.167.11.6292.

Abstract

The alpha-chain of the IL-15R (IL-15Ralpha) serves as the specific, high-affinity receptor for IL-15. It is expressed by lymphoid and nonlymphoid cells, including B cell lymphoma lines. In this study, we have further explored IL-15Ralpha-mediated signaling in activated primary B cells and in Raji cells, a human B-lymphoblastoid cell line which expresses the IL-15Ralpha and IL-2Rgamma chains, but lacks the IL-2Rbeta chain. Stimulation of Raji cells with IL-15 induces their proliferation and rescues them from C2-ceramide-induced apoptosis. By immunoprecipitation and Western blotting, we show that treatment of Raji cells and activated primary B cells with IL-15 induces coprecipitation of Syk kinase with the IL-15Ralpha chain. Upon association, the activated Syk kinase phosphorylates the IL-15Ralpha chain as well as phospholipase Cgamma, which coprecipitates with Syk. Furthermore, transfection of Raji cells with stem-loop Syk antisense oligonucleotides prevents IL-15Ralpha and phospholipase Cgamma phosphorylation as well as the inhibition of apoptosis by IL-15. Mutation of a defined region of the intracellular signaling portion of IL-15Ralpha (Tyr227) abrogates both the IL-15Ralpha/Syk association and IL-15Ralpha phosphorylation. Taken together, this suggests that Syk kinase physically and functionally associates with the IL-15Ralpha chain in B cells and that Syk plays a key role in mediating IL-15-induced signal transduction, thus accounting for the distinct functional consequences of IL-15 vs IL-2 binding to B cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Retracted Publication

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis / immunology
  • B-Lymphocyte Subsets / drug effects
  • B-Lymphocyte Subsets / enzymology
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / metabolism*
  • Calcium / antagonists & inhibitors
  • Calcium Signaling / genetics
  • Calcium Signaling / immunology
  • Cell Division / drug effects
  • Cell Division / immunology
  • Enzyme Activation / immunology
  • Enzyme Precursors / antagonists & inhibitors
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism*
  • Enzyme Precursors / physiology
  • Humans
  • Interleukin-15 / antagonists & inhibitors
  • Interleukin-15 / metabolism*
  • Interleukin-15 / physiology
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Jurkat Cells
  • K562 Cells
  • Lymphocyte Activation
  • Mutagenesis, Site-Directed
  • Oligonucleotides, Antisense / pharmacology
  • Phospholipase C gamma
  • Phosphorylation
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • Protein-Tyrosine Kinases / physiology
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2 / antagonists & inhibitors
  • Receptors, Interleukin-2 / biosynthesis
  • Receptors, Interleukin-2 / metabolism
  • Receptors, Interleukin-2 / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology*
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Syk Kinase
  • T-Lymphocyte Subsets / enzymology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Tumor Cells, Cultured
  • Type C Phospholipases / antagonists & inhibitors
  • Type C Phospholipases / metabolism
  • src Homology Domains / immunology

Substances

  • Enzyme Precursors
  • IL15RA protein, human
  • Interleukin-15
  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • N-acetylsphingosine
  • Oligonucleotides, Antisense
  • Receptors, Interleukin-15
  • Receptors, Interleukin-2
  • Protein-Tyrosine Kinases
  • SYK protein, human
  • Syk Kinase
  • Type C Phospholipases
  • Phospholipase C gamma
  • Sphingosine
  • Calcium