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.
Arch Dermatol Res
; 290(9): 501-7, 1998 Sep.
Article
em En
| MEDLINE
| ID: mdl-9808344
ABSTRACT
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).
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Citocinas
/
Tacrolimo
/
Imunofilinas
/
Mastócitos
/
Antibacterianos
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Animals
Idioma:
En
Revista:
Arch Dermatol Res
Ano de publicação:
1998
Tipo de documento:
Article
País de afiliação:
Alemanha