| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam;
Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory and Van Creveld Laboratory;
AIMM Therapeutics, B.V., Amsterdam, The Netherlands; and
Genentech, Inc., San Francisco, CA 94080
STAT family members have been implicated in regulating the balance between B cell lymphoma (BCL)6 and B lymphocyte induced maturation protein (BLIMP)1 to control plasma cell differentiation. We previously showed that STAT5 induces BCL6 to block plasma cell differentiation and extend the life span of human B cells. The heterogeneity in STAT activation by cytokines and their effects on B cell differentiation prompted us to investigate the effect of STAT3 activation in plasma cell differentiation. First stimulation with IL-21, which promotes plasma cell differentiation, induced robust and prolonged STAT3 activation in primary human B cells. We then investigated effects of direct STAT3 activation on regulation of plasma cell genes, cellular phenotype, and Ig production. Activation of a tamoxifen-regulated STAT3-estrogen receptor fusion protein triggered BLIMP1 mRNA and protein up-regulation, plasma cell phenotypic features, and Ig secretion. When STAT3 was activated by IL-21 in B cells ectopically expressing BCL6, BLIMP1 was up-regulated, but only partial plasma cell differentiation was achieved. Lastly, through coexpression of BCL6 and STAT3-ER, we verified that STAT3 activation functionally mimicked IL-21 treatment and that STAT3-mediated BLIMP1 up-regulation occurred despite high BCL6 expression levels indicating that BCL6 is not the dominant repressor of BLIMP1. Thus, up-regulation of BLIMP1 alone is not sufficient for differentiation of primary human B cells into plasma cells; concomitant down-regulation of BCL6 is absolutely required for completion of the plasma cell differentiation program.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work is supported by National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant F32AI063846 (to S.A.D).
2 Address correspondence and reprint requests to Dr. Hergen Spits, Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105AZ Amsterdam, The Netherlands. E-mail address: hergen.spits{at}amc.uva.nl
3 Abbreviations used in this paper: GC, germinal center; BCL, B cell lymphoma; BLIMP, B lymphocyte induced maturation protein; XBP, X-box-binding protein; CD40L-L, L cell fibroblasts stably expressing CD40L; 4-HT, 4-hydroxytamoxifen; p, phospho; WT, wild-type; LZRS, Lazarus; ER, estrogen receptor; IRES, internal ribosomal entry site; ivPC, in vitro-derived plasma cell; NGFR, nerve growth factor receptor.
This article has been cited by other articles:
|
|
 |
|
  M. A. J. Morgan, E. Magnusdottir, T. C. Kuo, C. Tunyaplin, J. Harper, S. J. Arnold, K. Calame, E. J. Robertson, and E. K. Bikoff Blimp-1/Prdm1 Alternative Promoter Usage during Mouse Development and Plasma Cell Differentiation Mol. Cell. Biol., November 1, 2009; 29(21): 5813 - 5827. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Frecha, C. Costa, C. Levy, D. Negre, S. J. Russell, A. Maisner, G. Salles, K.-W. Peng, F.-L. Cosset, and E. Verhoeyen Efficient and stable transduction of resting B lymphocytes and primary chronic lymphocyte leukemia cells using measles virus gp displaying lentiviral vectors Blood, October 8, 2009; 114(15): 3173 - 3180. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, G. Lin, J. S. Huo, D. Barney, Z. Wang, T. Livshiz, D. J. States, Z. S. Qin, and J. Schwartz Computational and Functional Analysis of Growth Hormone (GH)-Regulated Genes Identifies the Transcriptional Repressor B-Cell Lymphoma 6 (Bc16) as a Participant in GH-Regulated Transcription Endocrinology, August 1, 2009; 150(8): 3645 - 3654. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Dienz, S. M. Eaton, J. P. Bond, W. Neveu, D. Moquin, R. Noubade, E. M. Briso, C. Charland, W. J. Leonard, G. Ciliberto, et al. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells J. Exp. Med., January 16, 2009; 206(1): 69 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. T. Avery, C. S. Ma, V. L. Bryant, B. Santner-Nanan, R. Nanan, M. Wong, D. A. Fulcher, M. C. Cook, and S. G. Tangye STAT3 is required for IL-21-induced secretion of IgE from human naive B cells Blood, September 1, 2008; 112(5): 1784 - 1793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Scheeren, S. A. Diehl, L. A. Smit, T. Beaumont, M. Naspetti, R. J. Bende, B. Blom, K. Karube, K. Ohshima, C. J. M. van Noesel, et al. IL-21 is expressed in Hodgkin lymphoma and activates STAT5: evidence that activated STAT5 is required for Hodgkin lymphomagenesis Blood, May 1, 2008; 111(9): 4706 - 4715. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
