Facilitation of apoptosis by cyclosporins A and H, but not FK506 in mouse bronchial eosinophils.
This study was undertaken to clarify whether or not binding to cyclophilin is a prerequisite for cyclosporin A-induced modulation of apoptotic cell death in eosinophils. Eosinophils were isolated from bronchoalveolar lavage fluid of mice challenged with inhaled allergen after sensitization. Apoptosis was determined by analysing the DNA content. At 72 h, 99% of the cells had died without addition of cytokines, whereas 55-60% of the cells survived in the presence of 10 U/ml recombinant murine interleukin 5 or recombinant murine granulocyte macrophage-colony stimulation factor (GM-CSF). Apoptotic cell death at 72 h in the presence of 10 U/ml interleukin 5 was increased by addition of cyclosporin H, an analogue of cyclosporin A without cyclophilin binding activity, in a concentration-dependent (0.3 to 3 microM) manner. The increase in apoptosis elicited by cyclosporin A and cyclosporin H took place also in the presence of 10 U/ml GM-CSF but to a lesser extent. There was a significant augmentation of apoptosis in eosinophils cultured in the presence of each cytokine for 72 h or longer. Tacrolimus (FK506) failed to augment apoptotic cell death. Thus, it is unlikely that binding of cyclosporin A to cyclophilin accounts for the increased apoptosis induced by cyclosporin A and its analogue in eosinophils. The increase in apoptosis induced by cyclosporin A, but not FK506, in activated eosinophils from the airways may be attributed to the anti-asthmatic effects of cyclosporin A.
Kitagaki
K
K
Department of Pharmacology, Sandoz Tsukuba Res. Inst., Ohkubo, Japan.
Nagai
H
H
Hayashi
S
S
Totsuka
T
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001980:Bronchi / Q000166:cytology / Q000187:drug effects*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000378:metabolism / Q000494:pharmacology*; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D015848:Interleukin-5 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019696:Peptidylprolyl Isomerase / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D016559:Tacrolimus / Q000378:metabolism / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D015848:Interleukin-5; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D016572:Cyclosporine; D019696:Peptidylprolyl Isomerase; C050025:cyclosporin H; D016559:Tacrolimus