The Bcl10-Malt1 complex segregates Fc epsilon RI-mediated nuclear factor kappa B activation and cytokine production from mast cell degranulation.
Mast cells are pivotal effector cells in IgE-mediated allergic inflammatory diseases. Central for mast cell activation are signals from the IgE receptor FcepsilonRI, which induce cell degranulation with the release of preformed mediators and de novo synthesis of proinflammatory leukotrienes and cytokines. How these individual mast cell responses are differentially controlled is still unresolved. We identify B cell lymphoma 10 (Bcl10) and mucosa-associated lymphoid tissue 1 (Malt1) as novel key regulators of mast cell signaling. Mice deficient for either protein display severely impaired IgE-dependent late phase anaphylactic reactions. Mast cells from these animals neither activate nuclear factor kappaB (NF-kappaB) nor produce tumor necrosis factor alpha or interleukin 6 upon FcepsilonRI ligation even though proximal signaling, degranulation, and leukotriene secretion are normal. Thus, Bcl10 and Malt1 are essential positive mediators of FcepsilonRI-dependent mast cell activation that selectively uncouple NF-kappaB-induced proinflammatory cytokine production from degranulation and leukotriene synthesis.
Klemm
Stefanie
S
Third Medical Department, Klinikum rechts der Isar, Technical University of Munich, 81675 Munich, Germany.
Gutermuth
Jan
J
Hültner
Lothar
L
Sparwasser
Tim
T
Behrendt
Heidrun
H
Peschel
Christian
C
Mak
Tak W
TW
Jakob
Thilo
T
Ruland
Jürgen
J
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D020169:Caspases; D015550:Cell Degranulation / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D007073:Immunoglobulin E / Q000502:physiology; D050356:Lipid Metabolism / Q000235:genetics / Q000276:immunology; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D046912:Multiprotein Complexes / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017455:Receptors, IgE / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D016207:Cytokines; D046912:Multiprotein Complexes; D016328:NF-kappa B; D009363:Neoplasm Proteins; D017455:Receptors, IgE; D007073:Immunoglobulin E; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein