Inhibition of human B lymphocyte cell cycle progression and differentiation by rapamycin

Cell Immunol. 1994 Jul;156(2):493-507. doi: 10.1006/cimm.1994.1193.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibody-Producing Cells / cytology
  • Antibody-Producing Cells / drug effects
  • Antibody-Producing Cells / immunology
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / immunology
  • CD40 Ligand
  • CDC2 Protein Kinase / metabolism
  • CDC2-CDC28 Kinases*
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases*
  • DNA / biosynthesis
  • Humans
  • Immunosuppressive Agents / pharmacology*
  • In Vitro Techniques
  • Kinetics
  • Lymphocyte Activation / drug effects
  • Membrane Glycoproteins
  • Polyenes / pharmacology*
  • Protamine Kinase / antagonists & inhibitors
  • Protein Kinases / metabolism
  • Protein-Serine-Threonine Kinases*
  • RNA / biosynthesis
  • Sirolimus
  • Staphylococcus aureus / immunology
  • Tacrolimus / pharmacology

Substances

  • Immunosuppressive Agents
  • Membrane Glycoproteins
  • Polyenes
  • CD40 Ligand
  • RNA
  • DNA
  • Protein Kinases
  • Protamine Kinase
  • Protein-Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • CDC2-CDC28 Kinases
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2
  • Cyclin-Dependent Kinases
  • Sirolimus
  • Tacrolimus