Involvement of a rapamycin-sensitive pathway in CD40-mediated activation of murine B cells in vitro.
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.
Sakata
A
A
Department of Immunology, Kumamoto University School of Medicine, Japan.
Kuwahara
K
K
Ohmura
T
T
Inui
S
S
Sakaguchi
N
N
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects*; D019013:CD40 Antigens / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D004347:Drug Interactions; D007072:Immunoglobulin D / Q000302:isolation & purification; D007075:Immunoglobulin M / Q000302:isolation & purification; D007166:Immunosuppressive Agents / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011947:Receptors, Antigen, B-Cell / Q000302:isolation & purification; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000077191:Wortmannin
D000730:Androstadienes; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011947:Receptors, Antigen, B-Cell; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020123:Sirolimus; D000077191:Wortmannin