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International Immunology Advance Access originally published online on September 9, 2008
International Immunology 2008 20(11):1417-1426; doi:10.1093/intimm/dxn101
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© The Japanese Society for Immunology. 2008. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

PKC{eta} directs induction of IRF-4 expression and Ig {kappa} gene rearrangement in pre-BCR signaling pathway

Akihisa Oda1, Tomohiro Ono1, Mutsumi Yamamoto1,4, Ryo Goitsuka2 and Daisuke Kitamura1,3

1 Division of Molecular Biology
2 Division of Development and Aging, Research Institute for Biological Sciences
3 Faculty of Pharmaceutical Science, Tokyo University of Science, Noda, Chiba 278-0022, Japan
4 Present address: Department of Microbiology and Immunology, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA

Correspondence to: D. Kitamura; E-mail: kitamura{at}rs.noda.tus.ac.jp

Pre-B cell receptor (pre-BCR) signals promote pre-B cell differentiation, in which the adaptor protein B-cell linker (BLNK) plays a crucial role. However, the molecular pathways downstream of BLNK are currently unclear. Utilizing pre-B leukemia cell lines (BKO84 and others) derived from BLNK-deficient mice as in vitro models of the pre-B cell differentiation, we have demonstrated that reconstitution of BLNK as well as an active form of protein kinase C (PKC){eta} induces the differentiation events, such as pre-BCR down-regulation and {kappa} gene rearrangement. Here we show that the same events are induced by cross-linking of pre-BCR with anti-µ antibody in these pre-B cell lines, as well as in ex vivo pre-B cells from BLNK-deficient mice, suggesting a function of BLNK as an internal cross-linker of pre-BCR. Anti-µ treatment of BKO84 cells up-regulated membrane recruitment of PKC{eta} and the expression of IRF-4, a transcription factor known to promote light chain gene rearrangements. Anti-µ induction of surface {kappa} chain on BKO84 cells was blocked by reagents that inhibit phospholipase C or PKC. Enforced expression of the active PKC{eta} in BKO84 cells resulted in up-regulation of IRF-4 expression. Conversely, siRNA-mediated silencing of PKC{eta} expression strikingly attenuated the anti-µ-induced IRF-4 expression and {kappa} gene rearrangement, which were restored by PKC{eta} reconstitution. Finally, enforced expression of IRF-4, but not of BLNK, in the PKC{eta}-silenced BKO84 cells resulted in {kappa} gene rearrangement. These results indicate that PKC{eta} directs the induction of IRF-4 expression downstream of BLNK in the pre-BCR signaling pathway promoting {kappa} gene rearrangement.

Keywords: BLNK, Ig gene, pre-B cell, pre-B cell receptor, protein kinase C, signal transduction

Transmitting editor: T. Watanabe

Received 30 June 2008, accepted 11 August 2008.


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