TRAF6 specifically contributes to FcepsilonRI-mediated cytokine production but not mast cell degranulation.
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.
Yang
Yong Jun
YJ
Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia B3K 6R8, Canada.
Chen
Wei
W
Carrigan
Svetlana O
SO
Chen
Wei-Min
WM
Roth
Kristy
K
Akiyama
Taishin
T
Inoue
Jun-ichiro
J
Marshall
Jean S
JS
Berman
Jason N
JN
Lin
Tong-Jun
TJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007073:Immunoglobulin E / Q000276:immunology; D008099:Liver / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008407:Mast Cells / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism*; D013379:Substrate Specificity; D048029:TNF Receptor-Associated Factor 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D017455:Receptors, IgE; D048029:TNF Receptor-Associated Factor 6; D007073:Immunoglobulin E; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D002118:Calcium