The BH3-mimetic ABT-737 induces mast cell apoptosis in vitro and in vivo: potential for therapeutics.
Mast cells and their mediators are implicated in the pathogenesis of many different diseases. One possible therapeutic intervention in mast cell-associated diseases can be to reduce the number of tissue mast cells by inducing mast cell apoptosis. In this study, we demonstrate that mast cells exhibit a high sensitivity to ABT-737, a BH3-only mimetic molecule that induces apoptosis through high-affinity binding to the prosurvival proteins, Bcl-2, Bcl-XL, and Bcl-w. Primary mast cells as well as mast cell lines tested succumbed to apoptosis in response to the inhibitor at varying but seemingly low concentrations compared with other leukocytes investigated. I.p. injections of ABT-737 in mice resulted in a total abolishment of mast cells in the peritoneum. Confocal microscopy analysis of peritoneal cells revealed apoptotic bodies of mast cells being phagocytosed by macrophages. In addition, ex vivo treatment of human skin biopsies with ABT-737 demonstrated increased mast cell apoptosis. The data we present in this article show exceptional mast cell sensitivity to ABT-737, a selective inhibitor of antiapoptotic proteins, rendering a possible application for BH3-only mimetic compounds like ABT-737 in mast cell-associated diseases, such as mastocytosis, allergy, asthma, and other chronic inflammations.
Karlberg
Mats
M
Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Ekoff
Maria
M
Huang
David C S
DC
Mustonen
Paula
P
Harvima
Ilkka T
IT
Nilsson
Gunnar
G
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D015153:Blotting, Western; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009596:Nitrophenols / Q000494:pharmacology*; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000172:deficiency / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency / Q000235:genetics
C501332:ABT-737; C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein