Act1, a Negative Regulator in CD40- and BAFF-Mediated B Cell Survival
| Autor: | Robert L. Fairchild, Xiaoxia Li, E. Charles Snow, Sidne A. Omori, Youcun Qian, Brian L. Kotzin, Carl F. Ware, Robert C. Rickert, Martin L. Scott, Grace Cui, Mayumi Naramura, Jinzhong Qin |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
MAPK/ERK pathway
Cell Survival Lymphoid Tissue MAP Kinase Kinase 4 Transgene Blotting Western Immunology Enzyme-Linked Immunosorbent Assay Mice Transgenic macromolecular substances Biology p38 Mitogen-Activated Protein Kinases Receptors Tumor Necrosis Factor Mice Hypergammaglobulinemia B-Cell Activating Factor medicine Animals Immunoprecipitation Immunology and Allergy CD40 Antigens BAFF receptor B-cell activating factor Receptor B cell Autoantibodies Mice Knockout Mitogen-Activated Protein Kinase Kinases B-Lymphocytes CD40 Tumor Necrosis Factor-alpha JNK Mitogen-Activated Protein Kinases NF-kappa B Membrane Proteins Flow Cytometry Immunohistochemistry Cell biology Blotting Southern Infectious Diseases medicine.anatomical_structure Knockout mouse biology.protein I-kappa B Proteins Carrier Proteins B-Cell Activation Factor Receptor Signal Transduction |
| Zdroj: | Immunity. 21:575-587 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2004.09.001 |
| Popis: | TNF receptor (TNFR) superfamily members, CD40, and BAFFR play critical roles in B cell survival and differentiation. Genetic deficiency in a novel adaptor molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, and autoantibodies. While the B cell-specific Act1 knockout mice displayed a similar phenotype with less severity, the pathology of the Act1-deficient mice was mostly blocked in CD40-Act1 and BAFF-Act1 double knockout mice. CD40- and BAFF-mediated survival is significantly increased in Act1-deficent B cells, with stronger IκB phosphorylation, processing of NF-κB2 (p100/p52), and activation of JNK, ERK, and p38 pathways, indicating that Act1 negatively regulates CD40- and BAFF-mediated signaling events. These findings demonstrate that Act1 plays an important role in the homeostasis of B cells by attenuating CD40 and BAFFR signaling. |
| Databáze: | OpenAIRE |
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