| RRC ID |
36834
|
| Author |
Nagamachi A, Nakata Y, Ueda T, Yamasaki N, Ebihara Y, Tsuji K, Honda Z, Takubo K, Suda T, Oda H, Inaba T, Honda H.
|
| Title |
Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.
|
| Journal |
PLoS One
|
| Abstract |
A20 is a negative regulator of NF-κB, and mutational loss of A20 expression is involved in the pathogenesis of autoimmune diseases and B-cell lymphomas. To clarify the role of A20 in adult hematopoiesis, we generated conditional A20 knockout mice (A20(flox/flox) ) and crossed them with Mx-1Cre (MxCre (+)) and ERT2Cre (ERT2Cre (+)) transgenic mice in which Cre is inducibly activated by endogenous interferon and exogenous tamoxifen, respectively. A20(flox/flox) MxCre (+) (A20Mx) mice spontaneously exhibited myeloid proliferation, B cell apoptosis, and anemia with overproduction of pro-inflammatory cytokines. Bone marrow transplantation demonstrated that these changes were caused by hematopoietic cells. NF-κB was constitutively activated in A20Mx hematopoietic stem cells (HSCs), which caused enhanced cell cycle entry and impaired repopulating ability. Tamoxifen stimulation of A20(flox/flox) ERT2Cre (+) (A20ERT2) mice induced fulminant apoptosis and subsequent myeloproliferation, lymphocytopenia, and progressive anemia with excessive production of pro-inflammatory cytokines, as observed in A20Mx mice. These results demonstrate that A20 plays essential roles in the homeostasis of adult hematopoiesis by preventing apoptosis and inflammation. Our findings provide insights into the mechanism underlying A20 dysfunction and human diseases in which A20 expression is impaired.
|
| Volume |
9(1)
|
| Pages |
e87425
|
| Published |
2014-1-1
|
| DOI |
10.1371/journal.pone.0087425
|
| PII |
PONE-D-13-34927
|
| PMID |
24498102
|
| PMC |
PMC3909109
|
| MeSH |
Animals
Apoptosis / physiology*
Cell Proliferation*
Cysteine Endopeptidases
Cytokines / metabolism
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism*
Hematopoiesis / physiology*
Hematopoietic Stem Cells / cytology
Hematopoietic Stem Cells / metabolism*
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism*
Mice
Mice, Knockout
Myeloid Cells / cytology
Myeloid Cells / metabolism*
NF-kappa B / metabolism
Tumor Necrosis Factor alpha-Induced Protein 3
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
|
| IF |
2.74
|
| Times Cited |
16
|
|
WOS Category
|
IMMUNOLOGY
|
| Resource |
| Mice |
RBRC01834 |
