Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells.
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 CD38(low/int)CD23(int)HLA-DR(high)CD19(high)CD20(int) cell surface phenotype. Continued culture with IL-21 resulted in accumulation of cells in G(0)/G(1) stage of the cell cycle and increased apoptosis. This coincided with differentiation into small, CD38(high)CD23(low/-)HLA-DR(int)CD19(int)CD20(low) 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.
Konforte
Danijela
D
Division of Stem Cell and Developmental Biology, Princess Margaret Hospital, Ontario Cancer Institute, University Health Network, 610 University Avenue, Toronto, Ontario, Canada. konforte@uhnres.utoronto.ca
Paige
Christopher J
CJ
D001402:B-Lymphocytes / Q000166:cytology* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D016130:Immunophenotyping; D007378:Interleukins / Q000494:pharmacology* / Q000502:physiology; D053612:Janus Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000098546:Interleukin-21
D007378:Interleukins; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D050791:STAT Transcription Factors; D053612:Janus Kinases; D000098546:Interleukin-21