The antiallergic drug oxatomide promotes human eosinophil apoptosis and suppresses IL-5-induced eosinophil survival.
BACKGROUND
Eosinophils accumulated in sites of allergic inflammation are thought to play a crucial role in the pathogenesis of allergic disorders including asthma, allergic rhinitis, and atopic dermatitis, and tissue eosinophilia is attributable to increased eosinophil survival or decreased eosinophil apoptosis.


OBJECTIVE
Effects of the antiallergic, histamine H1 blocker oxatomide on viability and apoptosis of eosinophils isolated from the peripheral blood of atopic subjects were studied.


METHODS
Eosinophil viability and apoptosis were evaluated by using a colorimetric assay and annexin V-labeling, caspase-3 activity, and DNA fragmentation assay.


RESULTS
The viability of eosinophils increased in the presence of IL-5 (10 ng/mL), confirming that IL-5 prolongs eosinophil survival in vitro. Application of oxatomide at concentrations over 20 micromol/L for 24 hours decreased the IL-5-induced enhancement of eosinophil viability. Double staining of the cells with annexin V and propidium iodide showed that deprivation of IL-5 promoted spontaneous eosinophil apoptosis and that oxatomide facilitated apoptosis and suppressed the prolongation of eosinophil survival stimulated by IL-5. In the absence of IL-5, approximately 71% and 96% of eosinophils after 24 and 48 hours, respectively, underwent spontaneous apoptosis. IL-5 decreased the rate of eosinophil apoptosis to 38% and 52% after 24 and 48 hours, respectively. Oxatomide increased eosinophil apoptosis in a concentration-dependent manner in the presence of IL-5. Furthermore, oxatomide increased caspase-3 activity and DNA fragmentation.


CONCLUSIONS
We demonstrated that oxatomide possesses a novel therapeutic effect of apoptosis promotion on eosinophils and prevents the antiapoptotic effects of IL-5, suggesting that oxatomide may contribute to resolution of tissue eosinophilia in allergic inflammation.
Domae
Mariko
M
Department of Pharmacology, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Sagara
Hironori
H
Sakaue
Morito
M
Fukuda
Takeshi
T
Kamikawa
Yuichiro
Y
D018926:Anti-Allergic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004804:Eosinophils / Q000502:physiology*; D006801:Humans; D006967:Hypersensitivity / Q000097:blood*; D015848:Interleukin-5 / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D013997:Time Factors
D018926:Anti-Allergic Agents; D015848:Interleukin-5; D010879:Piperazines; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C015408:oxatomide