Suppression of B cell activation by cyclosporin A, FK506 and rapamycin.
The effects of the immunosuppressants cyclosporin A (CsA), FK506 and rapamycin have been compared using murine B cells activated with a variety of mitogens. FK506 is a macrolide antibiotic that has been recently shown to inhibit T cell activation by a mechanism that appears similar to that of CsA. Rapamycin is a macrolide structurally related to FK506 whose mechanism of T cell suppression appears to be distinct from that of FK506 and CsA. While CsA and FK506 were found to preferentially inhibit B cell activation caused by stimuli which induce a rise in intracellular calcium, rapamycin partially inhibited activation by all stimuli tested, including those which are not associated with a calcium flux. All three compounds were found to inhibit cell cycle progression within the G1 phase; however, the rapamycin-sensitive event within G1 was completed earlier than the G1 events inhibited by CsA and FK506. In addition, inhibition of anti-IgM-activated B cells with CsA and FK506, but not with rapamycin, resulted in cell death. These data suggest that although CsA, FK506 and rapamycin are all inhibitors of B cell activation, the inhibitory activity of rapamycin can be clearly distinguished from that of CsA and FK506. Although the suppressive effects of CsA and FK506 on B cell proliferation were nearly identical in this study, their biological activities were distinguishable since FK506, but not CsA, could antagonize rapamycin-mediated suppression.
Department of Immunology Research, Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey 07065.
L S
LS
Wicker
R C
RC
Boltz
V
V
Matt
E A
EA
Nichols
L B
LB
Peterson
N H
NH
Sigal
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003524:Cyclosporins / Q000494:pharmacology*; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011090:Polyenes / Q000494:pharmacology; D020123:Sirolimus; D016559:Tacrolimus
D000900:Anti-Bacterial Agents; D000911:Antibodies, Monoclonal; D003524:Cyclosporins; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D011090:Polyenes; D020123:Sirolimus; D016559:Tacrolimus