| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Division of Stem Cell and Developmental Biology, Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, Toronto, Canada; and Department of Immunology, University of Toronto, Toronto, Canada
The complex process of B cell development is controlled by multiple factors from the surrounding microenvironment including cytokines. IL-21 is a recently identified type I cytokine, mainly produced by activated CD4+ T cells. It has been shown to promote differentiation of human primary B cells into Ig-secreting plasma cells. The objective of our study was to describe cellular intermediates that exist during IL-21-induced transition from an activated B cell to an Ig-secreting cell and to identify molecular mechanisms involved in this process. Novel Epstein-Barr Virus-positive human B cell lines with phenotypes characteristic of Ag-activated IgG+ B cell blasts were used as a model system to study IL-21 effects in vitro. We show that IL-21 increased both proliferation and survival of B cell lines during the first 3 days of in vitro culture. This process was associated with CD38low/intCD23intHLA-DRhighCD19highCD20int cell surface phenotype. Continued culture with IL-21 resulted in accumulation of cells in G0/G1 stage of the cell cycle and increased apoptosis. This coincided with differentiation into small, CD38highCD23low/–HLA-DRintCD19intCD20low late plasmablasts/early plasma cells that expressed lower levels of c-Myc protein, and secreted greater amounts of Ig than the control cells. Partial inhibition of IL-21-induced JAK/STAT signaling by the low-dose pharmacological agent, JAK inhibitor I, did not prevent the initial increase in proliferation. However, decrease in c-Myc protein expression and subsequent differentiation to late plasmablasts/early plasma cells were strongly inhibited. Our study is the first to show the link between IL-21-induced JAK/STAT signaling, c-Myc regulation, and differentiation of human B cells.
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 was supported by grants from the National Cancer Institute of Canada and the Canadian Institute of Health Research.
2 Address correspondence and reprint requests to Dr. Danijela Konforte, Division of Stem Cell and Developmental Biology, Princess Margaret Hospital, Ontario Cancer Institute, No. 8-105, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. E-mail address: konforte{at}uhnres.utoronto.ca
3 Abbreviations used in this paper: 
c, common cytokine receptor -chain; PC, plasma cell; BCL, B cell line; JAKi I, JAK inhibitor I; PB, peripheral blood; PI, propidium iodide; Ta, annealing temperature; DLBL, diffuse large B cell lymphoma; MM, multiple myeloma; GC, germinal center; TF, transcription factor; sIg, surface Ig.
This article has been cited by other articles:
|
|
 |
|
  S. A. Diehl, H. Schmidlin, M. Nagasawa, S. D. van Haren, M. J. Kwakkenbos, E. Yasuda, T. Beaumont, F. A. Scheeren, and H. Spits STAT3-Mediated Up-Regulation of BLIMP1 Is Coordinated with BCL6 Down-Regulation to Control Human Plasma Cell Differentiation J. Immunol., April 1, 2008; 180(7): 4805 - 4815. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. de Totero, R. Meazza, M. Capaia, M. Fabbi, B. Azzarone, E. Balleari, M. Gobbi, G. Cutrona, M. Ferrarini, and S. Ferrini The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways Blood, January 15, 2008; 111(2): 517 - 524. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
