Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin.
In this study, we have analyzed the effects of the immunosuppressive agent rapamycin on the activation of highly purified normal human B lymphocytes. When the polyclonal activators Staphylococcus aureus (SA) and soluble CD40 ligand (CD40L) were used to stimulate B cells, rapamycin inhibited both interleukin 2 (IL2)-dependent and -independent proliferation, as well as IL2-dependent differentiation into antibody-secreting cells. Cell cycle analysis indicated that rapamycin inhibited the progression of SA+IL2-stimulated B cells past the mid-G1 phase of the cell cycle. To begin to identify rapamycin-sensitive signaling events essential for B cell activation, we examined the effects of rapamycin on p34cdc2 and p33cdk2 kinase activities. SA+IL2 stimulation induced the activation of both cyclin-dependent kinases. Of interest, rapamycin abrogated the activation of both p34cdc2 and p33cdk2. Our results indicate therefore that rapamycin inhibits a number of SA- and CD40L-inducible events that may be necessary for both entry into S phase and for permitting subsequent B cell differentiation. These studies emphasize the utility of this drug as a tool to begin to dissect the activation pathways utilized by human B cells, as well as to provide implications for the therapeutic use of rapamycin in vivo.
Aagaard-Tillery
K M
KM
Department of Immunology, Mayo Clinic/Foundation, Rochester, Minnesota 55905.
Jelinek
D F
DF
D000328:Adult; D000921:Antibody-Producing Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D023201:CD40 Ligand; D016203:CDC2 Protein Kinase / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D004247:DNA / Q000096:biosynthesis; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins; D011090:Polyenes / Q000494:pharmacology*; D006656:Protamine Kinase / Q000037:antagonists & inhibitors; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D012313:RNA / Q000096:biosynthesis; D020123:Sirolimus; D013211:Staphylococcus aureus / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology
D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D011090:Polyenes; D023201:CD40 Ligand; D012313:RNA; D004247:DNA; D011494:Protein Kinases; D006656:Protamine Kinase; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020123:Sirolimus; D016559:Tacrolimus