TRAF6 specifically contributes to FcepsilonRI-mediated cytokine production but not mast cell degranulation

J Biol Chem. 2008 Nov 14;283(46):32110-8. doi: 10.1074/jbc.M802610200. Epub 2008 Sep 4.

Abstract

TRAF6 (tumor necrosis factor-associated factor 6) is an essential adaptor downstream from the tumor necrosis factor (TNF) receptor and Toll-like receptor superfamily members. This molecule is critical for dendritic cell maturation and T cell homeostasis. Here we show that TRAF6 is important in high affinity IgE receptor, FcepsilonRI-mediated mast cell activation. In contrast to dendritic cells and T cells, TRAF6-deficient mast cells matured normally and showed normal IgE-dependent degranulation. Importantly, TRAF6-deficient mast cells showed impaired production of cytokine interleukin-6, CCL-9, interleukin-13, and TNF following FcepsilonRI aggregation. Chromatin immunoprecipitation assay showed decreased NF-kappaB p65 binding to CCL-9 and TNF promoters in TRAF6-deficient mast cells. Antigen and IgE-induced IkappaB phosphorylation and NF-kappaB p65 translocation to the nucleus were diminished in TRAF6-deficient mast cells. NF-kappaB luciferase activity in response to antigen and IgE stimulation was severely impaired in TRAF6-deficient mast cells. In addition, antigen and IgE-induced phosphorylation of mitogen-activated protein kinase p38 and JNK, but not ERK1/2, was significantly reduced in TRAF6-deficient mast cells. These results identified TRAF6 as an important signal transducer in FcepsilonRI-mediated signaling in mast cells. Our findings implicate TRAF6 as a new adaptor/regulator molecule for allergen-mediated inflammation in allergy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Degranulation
  • Cell Line
  • Cytokines / biosynthesis*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Immunoglobulin E / immunology
  • Liver / metabolism
  • MAP Kinase Kinase 4 / metabolism
  • Mast Cells / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Receptors, IgE / immunology
  • Receptors, IgE / metabolism*
  • Substrate Specificity
  • TNF Receptor-Associated Factor 6 / deficiency
  • TNF Receptor-Associated Factor 6 / genetics
  • TNF Receptor-Associated Factor 6 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Cytokines
  • Receptors, IgE
  • TNF Receptor-Associated Factor 6
  • Immunoglobulin E
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4
  • Calcium