title: Ketotifen induces primary necrosis of human eosinophils.
abstract: Eosinophils are considered essential in the pathogenesis of allergy. Reduced eosinophil apoptosis is considered to be a key element in the formation of eosinophilia in allergic conditions. Antihistamines are widely used in the treatment of allergic disorders, but their effects on eosinophil apoptosis are poorly understood. The histamine H1-receptor antagonist, ketotifen, is available orally and as eye drops for the treatment of allergic symptoms. The aim of our study was to investigate the possible effect of ketotifen on constitutive eosinophil apoptosis and on interleukin (IL)-5-mediated eosinophil survival. Isolated peripheral blood eosinophils were cultured with or without the survival-prolonging cytokine IL-5 and ketotifen. Apoptosis was assessed by measuring the relative DNA content and by morphological analysis. Ketotifen was found to reverse eosinophil survival induced by interleukin-5. However, the flow cytometry histogram of DNA in propidium iodide-stained cells was not typical to apoptosis. Morphological analysis of the eosinophils by bright-field microscopy suggested that the effect of ketotifen was due to the induction of primary necrosis rather than apoptosis. Histological assessment of eosinophil ultrastructure by transmission electron microscopy confirmed signs of advanced necrosis. In summary, our results suggest that at clinically relevant drug concentrations, ketotifen induces primary necrosis in IL-5-treated human eosinophils.
authors.affiliation: The Immunopharmacological Research Group, Medical School, University of Tampere, Tampere, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Hasala
authors.forename: Hannele
authors.initials: H
authors.lastname: Hasela
authors.forename: Monika
authors.initials: M
authors.lastname: Malm-Erjefält
authors.forename: Jonas
authors.initials: J
authors.lastname: Erjefält
authors.forename: Mark A
authors.initials: MA
authors.lastname: Giembycz
authors.forename: Xianzhi
authors.initials: X
authors.lastname: Zhang
authors.forename: Eeva
authors.initials: E
authors.lastname: Moilanen
authors.forename: Hannu
authors.initials: H
authors.lastname: Kankaanranta
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D004804:Eosinophils / Q000187:drug effects* / Q000648:ultrastructure; D005434:Flow Cytometry; D006634:Histamine H1 Antagonists / Q000009:adverse effects*; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D007665:Ketotifen / Q000009:adverse effects*; D046529:Microscopy, Electron, Transmission; D009336:Necrosis
chemical_list: D006634:Histamine H1 Antagonists; D015848:Interleukin-5; D004247:DNA; D007665:Ketotifen