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PLoS One. 2014 Jan 31;9(1):e87425. doi: 10.1371/journal.pone.0087425. eCollection 2014.

Acquired deficiency of A20 results in rapid apoptosis, systemic inflammation, and abnormal hematopoietic stem cell function.

Author information

1
Department of Molecular Oncology, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
2
Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan.
3
Division of Cellular Therapy, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
4
Health Care Center and Graduate School of Humanities and Sciences, Institute of Environmental Science for Human Life, Ochanomizu University, Bunkyo-ku, Tokyo, Japan.
5
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
6
Department of Pathology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan.

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.

PMID:
24498102
PMCID:
PMC3909109
DOI:
10.1371/journal.pone.0087425
[Indexed for MEDLINE]
Free PMC Article
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