Inhibitory effects of ketotifen on eotaxin-dependent activation of eosinophils: consequences for allergic eye diseases.
BACKGROUND
The aim of this study was to investigate the effects of ketotifen on different parameters of human eosinophil functions, namely chemotaxis, oxidative metabolism and mediator release, induced after activation.


METHODS
Eosinophils from hypereosinophilic patients or normal donors were purified by Percoll gradient and the magnetic cell separation system. Chemotaxis was studied using the Boyden chamber technique using three potent chemoattractants: formyl-methionine-leucine-phenylalanine (fMLP), interleukin (IL)-5 and eotaxin. Oxidative metabolism was determined by a luminol-dependent chemiluminescence assay after activation with eotaxin or secretory immunoglobulin A (sIgA). The release of eosinophil cationic protein (ECP) and eosinophil derived neurotoxin (EDN) was measured by radioimmunoassay after activation with sIgA.


RESULTS
At pharmacologically active concentrations and in a dose-dependent manner, ketotifen significantly inhibited the chemotaxis of eosinophils to fMLP, IL-5 and eotaxin. The production of reactive oxygen species induced by eotaxin and sIgA was decreased by ketotifen, showing a more pronounced effect when cells were activated by eotaxin. Activation by sIgA resulted in ECP and EDN release, which was partially inhibited by ketotifen.


CONCLUSIONS
Through inhibition of chemotaxis, ketotifen might limit the number of eosinophils at the inflammation site during allergic reaction. Furthermore, inhibition by ketotifen of main inflammatory mediators release suggests a potential role of the drug in limiting the pathological potential of eosinophils.
Woerly
G
G
Centre d'Immunologie et Biologie Parasitaire, Unité INSERM-IPL U547, Institut Pasteur, Lille, France.
Loiseau
S
S
Loyens
M
M
Schoch
C
C
Capron
M
M
D018926:Anti-Allergic Agents / Q000494:pharmacology*; D001798:Blood Proteins / Q000187:drug effects; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000037:antagonists & inhibitors; D002631:Chemotactic Factors, Eosinophil; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D047208:Eosinophil-Derived Neurotoxin; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism; D005128:Eye Diseases / Q000188:drug therapy; D006801:Humans; D015848:Interleukin-5 / Q000037:antagonists & inhibitors; D007665:Ketotifen / Q000494:pharmacology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000037:antagonists & inhibitors; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D012260:Ribonucleases / Q000187:drug effects
D018926:Anti-Allergic Agents; D001798:Blood Proteins; C515456:CCL11 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D002631:Chemotactic Factors, Eosinophil; D015848:Interleukin-5; D017382:Reactive Oxygen Species; D009240:N-Formylmethionine Leucyl-Phenylalanine; D047208:Eosinophil-Derived Neurotoxin; D012260:Ribonucleases; D007665:Ketotifen