A pivotal role of cyclin D3 and cyclin-dependent kinase inhibitor p27 in the regulation of IL-2-, IL-4-, or IL-10-mediated human B cell proliferation.
The functional differences between IgDhighCD38- naive and IgD-CD38- memory (M) or IgDlowCD38+ germinal center (GC) B cells may stem from their variable response to signals that regulate activation, proliferation, and differentiation. In this report, we provide evidence for differential induction of cell cycle regulators in tonsillar human B cell subpopulations that were activated with anti-IgM and anti-CD40 in the presence or absence of IL-2, IL-4, or IL-10. Naive (IgDhigh) B cells exhibited a significant proliferative response to IL-4, but not to IL-2 or IL-10, whereas these cytokines triggered variable levels of growth in the combined GC/M subpopulation (referred to as IgDlow), as measured by [3H]thymidine incorporation. Induction of growth by cytokines in B cell subpopulations strictly correlated with the increased levels of cyclin D3 and cyclin-dependent protein kinase (cdk) 6. Moreover, only cyclin D3/cdk6 complexes were functional as observed in both naive and GC/M B cells stimulated in the presence of IL-4. In addition, active growth was associated with cytokine-mediated elimination of the cell cycle inhibitor p27. The significance of p27 in human B cell cycle was further demonstrated by rapamycin-mediated growth inhibition of IL-4-dependent proliferation, which resulted in strikingly increased p27 levels. Taken together, our findings suggest that cyclin D3, cdk6, and p27 play key roles in IL-2-, IL-4-, and IL-10-mediated human B cell proliferation. Furthermore, these results may provide a molecular basis for different cycling characteristics of naive and GC/M B cell subpopulations.
Department of Pediatrics, Women and Infants' Hospital-Brown University, Providence, RI 02905, USA.
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EF
Wagner
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Hleb
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N
Hanna
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Sharma
D000888:Antibodies, Anti-Idiotypic / Q000502:physiology; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000032:analysis / Q000037:antagonists & inhibitors*; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D056743:Cyclin D3; D051361:Cyclin-Dependent Kinase 6; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000032:analysis / Q000494:pharmacology*; D016193:G1 Phase / Q000276:immunology; D006801:Humans; D007072:Immunoglobulin D / Q000096:biosynthesis; D007075:Immunoglobulin M / Q000276:immunology; D016753:Interleukin-10 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D007378:Interleukins / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D014066:Palatine Tonsil / Q000166:cytology; D011090:Polyenes / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000502:physiology; D011506:Proteins; D020123:Sirolimus; D025521:Tumor Suppressor Proteins
D000888:Antibodies, Anti-Idiotypic; C534696:CCND3 protein, human; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D016213:Cyclins; D004791:Enzyme Inhibitors; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D007376:Interleukin-2; D007378:Interleukins; D008869:Microtubule-Associated Proteins; D011090:Polyenes; D011506:Proteins; D025521:Tumor Suppressor Proteins; C044203:anti-IgM; D016753:Interleukin-10; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015847:Interleukin-4; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases; D020123:Sirolimus