Ascomycin macrolactam derivative SDZ ASM 981 inhibits the
release of granule-associated mediators and of newly synthesized cytokines in
RBL 2H3 mast cells in an immunophilin-dependent manner.
Hultsch T, Muller KD, Meingassner JG, Grassberger M, Schopf RE, Knop J.
University Hautklinik Mainz, Germany.
Mast cells play an important role in the pathological development of many
inflammatory and allergic diseases and inhibition of mast cell activation is a
potential target for therapeutic intervention. Therefore, the effect of the
novel ascomycin macrolactam derivative SDZ ASM 981 on Fc epsilonRI-mediated
activation of rat basophilic leukemia (RBL) cells, as a model for mast cell
activation, was investigated. First, the ability to inhibit different mast cell
immunophilins in vitro was tested. Using recombinant macrophilin-12 (FKBP-12),
inhibition of rotamase activity with an IC50 of approximately 6 nM was observed.
The rotamase activity of cyclophilin A (18 kDa) was not affected. Secondly, the
effect of SDZ ASM 981 on Fc epsilonRI-mediated mast cell activation was
investigated in the RBL cell model. SDZ ASM 981 inhibited exocytosis of
preformed mediators (e.g. serotonin) with an IC50 of approximately 30 nM.
Transcription and release of newly synthesized mediators (e.g. TNF-alpha) was
inhibited with an IC50 of approximately 100 nM. The inhibitory effect of SDZ ASM
981 was antagonized by rapamycin. We conclude that SDZ ASM 981 is a potent
inhibitor of Fc epsilonRI-mediated activation of mast cells in vitro. The
mechanism of action involves formation of (calcineurin) inhibitory complexes
with macrophilins. We suggest that this inhibitory action on mast cells might
contribute to the antiinflammatory effect of SDZ ASM 981 observed in vivo (e.g.
in aptopic dermatitis and psoriasis).