Suppression of B cell activation by cyclosporin A, FK506 and rapamycin

Abstract

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.

Proliferation and Survival of Activated B Cells Requires Sustained Antigen Receptor Engagement and Phosphoinositide 3-Kinase Activation

“…Inhibitor studies have also suggested a late requirement for both mTOR and calcineurin activity in activated murine B cells (19). Similarly, we found that addition of the calcineurin inhibitor FK506 to anti-IgM-stimulated cells reduced proliferation, with ϳ80% inhibition relative to the diluent-treated control even at 40 h (Fig.…”

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

“…Binding of this complex to the mTOR protein results in the dissociation of mTORC1, thereby inhibiting its ability to phosphorylate downstream substrates ( Figure 5) (Chung et al, 1992). Due to its ability to inhibit T-and B-cell proliferation and activation (Dumont et al, 1990;Wicker et al, 1990), rapamycin and its analogs RAD001 (everolimus) and CCI-779 (temsirolimus) have been approved by the Food and Drug Administration (FDA) as immunosuppressive agents in the United States, and is now commercially available. In addition, these drugs appear to affect tumor growth by inducing tumor cell apoptosis and suppressing angiogenesis (Law, 2005).…”

Rapamycin is active against B-precursor leukemiain vitroandin vivo, an effect that is modulated by IL-7-mediated signaling

“…Rapamycin (sirolimus, Rapamune) is a naturally occurring immunosuppressive macrocyclic lactone that is structurally related to but biochemically distinct from FK506 (tacrolimus, Prograf) (32,33). Rapamycin inhibits the induction of activation and proliferation of mature T and B cells and is used as an immunosuppressive agent after solid organ transplant (34 -38).…”