Involvement of a rapamycin-sensitive pathway in CD40-mediated activation of murine B cells in vitro

Immunol Lett. 1999 Jun 1;68(2-3):301-9. doi: 10.1016/s0165-2478(99)00053-x.

Abstract

Activation of resting B cells requires an initial triggering of the B cell antigen receptor (BCR) and secondary stimuli through various cytokine receptors and B cell activation molecules including CD40. We found that activation of B cells through CD40 is selectively inhibited by an immunosuppressant drug, rapamycin. This effect of rapamycin on anti-CD40-mediated activation of B cells was observed using three different in vitro assays. Rapamycin suppressed the anti-CD40-induced proliferation of splenic B cells, suppressed differentiation to surface IgMhigh/IgDlow B cells, and inhibited an anti-CD40-mediated prevention of apoptosis induced by BCR cross-linkage of WEHI-231 cells. We next examined several known CD40 signal transduction pathways to identify the target of rapamycin in stimulated B cells. Rapamycin did not inhibit the activation of c-Jun N-terminal kinases (JNKs) induced by anti-CD40 stimulation nor the activation of immediate nuclear transcription factors of NF-kappaB. Therefore, rapamycin affects a novel element of the CD40 signal transduction pathway which influences the proliferation, differentiation, and prevention of apoptosis of B cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstadienes / pharmacology
  • Animals
  • Antigens, Differentiation, B-Lymphocyte
  • Apoptosis / drug effects
  • B-Lymphocytes / drug effects*
  • CD40 Antigens / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Drug Interactions
  • Immunoglobulin D / isolation & purification
  • Immunoglobulin M / isolation & purification
  • Immunosuppressive Agents / pharmacology
  • JNK Mitogen-Activated Protein Kinases
  • Lymphocyte Activation / drug effects*
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases*
  • NF-kappa B / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Antigen, B-Cell / isolation & purification
  • Signal Transduction
  • Sirolimus / pharmacology*
  • Spleen / cytology
  • Spleen / immunology
  • Wortmannin

Substances

  • Androstadienes
  • Antigens, Differentiation, B-Lymphocyte
  • CD40 Antigens
  • Immunoglobulin D
  • Immunoglobulin M
  • Immunosuppressive Agents
  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Receptors, Antigen, B-Cell
  • Calcium-Calmodulin-Dependent Protein Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Sirolimus
  • Wortmannin