First-generation antihistamines diphenhydramine and chlorpheniramine reverse cytokine-afforded eosinophil survival by enhancing apoptosis

Antihistamines or histamine H₁-receptor antagonists are commonly used to treat a variety of allergic symptoms. Eosinophils are considered to play an essential role in the pathogenesis of allergy. Reduced eosinophil apoptosis is thought to be an important element in the formation of eosinophilia in allergic conditions such as allergic rhinitis, atopic eczema, and asthma. The aim of this study was to investigate the effects of two first-generation antihistamines diphenhydramine and chlorpheniramine on constitutive eosinophil apoptosis and on interleukin (IL)-5–afforded eosinophil survival. The role of c-Jun N-terminal kinase (JNK) in mediating the effects of antihistamines on eosinophil apoptosis was evaluated also. Apoptosis of isolated human eosinophils was assessed by measuring the relative DNA content of propidium iodide–stained cells and confirmed by morphological analysis. The activity of JNK was measured by Western blotting. Antihistamines were found to reverse the survival-prolonging effect of IL-5 in eosinophils by enhancing apoptosis. JNK was found to be activated slowly during diphenhydramine-induced eosinophil apoptosis. An inhibitor peptide specific for JNK, L-JNKI1 (JNK peptide inhibitor 1, L-stereoisomer), inhibited diphenhydramine-mediated eosinophil apoptosis. Our results suggest that first-generation antihistamines diphenhydramine and chlorpheniramine reverse IL-5–afforded eosinophil survival and that the enhanced apoptosis by antihistamines is mediated through activation of JNK. Thus, reversal of IL-5–afforded eosinophil survival may contribute to the antiallergic actions of diphenhydramine and chlorpheniramine.