Lacking of Aiolos accelerates pre-mature B cell apoptosis mediated by BCR signaling through elevation in cytochrome c release.
Antigen binding to B cell receptor (BCR) of pre-mature B lymphocytes leads to their apoptosis, while binding to BCR of mature B lymphocytes induces their activation and proliferation. The former binding is believed to be a mechanism so as to exclude B cell clones leading to protection from auto-immune diseases. Cross-linking of BCR of pre-mature B cells, including chicken DT40 cells, with anti-immunoglobulin antibody induces their apoptosis. The PMA/ionomycin treatments, which mimic BCR stimulation, are used to study intracellular signal transduction of B lymphocytes. Here, by analyzing the Aiolos-deficient DT40 cell line, Aiolos(-/-), we reveal that the lack of Aiolos accelerates apoptosis of DT40 cells mediated by BCR signaling. Moreover, the Aiolos-deficiency and BCR signaling cooperatively control this apoptosis through dramatically elevated cytochrome c release from mitochondria to cytosol and elevated caspase (caspase-3, 8 and 9) activities, resulting in drastically diminished amounts of ICAD followed by increased DNA fragmentation. Re-expression study reveals that the shorter isoform of Aiolos (Aio-2) controls PMA/ionomycin-mediated apoptosis via up-regulation and down-regulation of the PKCdelta and bak genes, respectively. These findings could be a powerful trigger to resolve molecular mechanisms of negative selection of B lymphocytes and also auto-immune diseases.
Department of Life Science, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan.
Hidehiko
H
Kikuchi
Koki
K
Yamashita
Masami
M
Nakayama
Kenji
K
Toyonaga
Isao
I
Tsuneyoshi
Mayumi
M
Takasaki
Tatsuo
T
Nakayama
D000818:Animals; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D002642:Chick Embryo; D045304:Cytochromes c / Q000378:metabolism*; D005434:Flow Cytometry; D051740:Ikaros Transcription Factor; D015151:Immunoblotting; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000502:physiology*
C491396:Ikzf3 protein, mouse; D007476:Ionophores; D012333:RNA, Messenger; D011947:Receptors, Antigen, B-Cell; D015534:Trans-Activators; D051740:Ikaros Transcription Factor; D015759:Ionomycin; D045304:Cytochromes c; D020169:Caspases