Effects of cyclosporin A and FK-506 on stem cell factor-induced histamine secretion and growth of human mast cells.
Stem cell factor (SCF) is a key regulator of human mast cells (MCs) and a potential mediator of allergy. In this study the effects of cyclosporin A (CSA) and FK-506, two potent immunosuppressive drugs, on SCF-dependent histamine release and growth of human MCs were analyzed. Preincubation of tissue MCs with CSA (3 micrograms/ml) resulted in inhibition of histamine release provoked by either recombinant human (rh) SCF (70.3% +/- 20.6% inhibition, p < 0.001) or anti-IgE (76.7% +/- 21.9%, p < 0.001) or by rhSCF+ anti-IgE (77.4% +/- 13.9%, p < 0.001). Almost the same inhibition was produced by FK-506 (rhSCF: 82.0% +/- 18.9% inhibition, p < 0.001; anti-IgE: 71.5% +/- 16.7%, p < 0.001; rhSCF+ anti-IgE: 70.0% +/- 7.3%, p < 0.001). The effects of CSA and FK-506 on SCF-dependent release of histamine were dose-dependent (IC50: CSA, 1 to 10 ng/ml; FK-506, 0.3 to 3 ng/ml). IC50 values about three to 10 times higher were found for MCs preincubated with rhSCF before anti-IgE activation, compared with anti-IgE or SCF alone. SCF-dependent differentiation of human MCs was analyzed in a long-term suspension culture system (n = 6). Unexpectedly, CSA and FK-506 were unable to suppress, but even enhanced SCF-dependent growth of MCs and formation of MC tryptase in long-term culture. Together, CSA and FK-506 inhibit SCF-dependent release of histamine from human MCs and even augment SCF-dependent growth of human MCs in long-term culture.
Sperr
W R
WR
Department of Internal Medicine I, University of Vienna, Austria.
Agis
H
H
Czerwenka
K
K
Virgolini
I
I
Bankl
H C
HC
Müller
M R
MR
Zsebo
K
K
Lechner
K
K
Valent
P
P
D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D000242:Cyclic AMP / Q000096:biosynthesis; D016572:Cyclosporine / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects*; D006801:Humans; D007946:Leukemia, Mast-Cell; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis / Q000187:drug effects; D019089:Stem Cell Factor / Q000187:drug effects / Q000502:physiology*; D016559:Tacrolimus / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D019089:Stem Cell Factor; D016572:Cyclosporine; D000242:Cyclic AMP; D019009:Proto-Oncogene Proteins c-kit; D016559:Tacrolimus