Hasala Hannele, Moilanen Eeva, Janka-Junttila Mirkka, Giembycz Mark A, Kankaanranta Hannu
The Immunopharmacology Research Group, Medical School, Tampere University Hospital, Tampere, Finland.
Allergy Asthma Proc. 2007 Jan-Feb;28(1):79-86. doi: 10.2500/aap.2007.28.2961.
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.
抗组胺药或组胺H1受体拮抗剂常用于治疗各种过敏症状。嗜酸性粒细胞被认为在过敏发病机制中起重要作用。嗜酸性粒细胞凋亡减少被认为是过敏性鼻炎、特应性皮炎和哮喘等过敏疾病中嗜酸性粒细胞增多形成的重要因素。本研究的目的是调查两种第一代抗组胺药苯海拉明和氯苯那敏对组成性嗜酸性粒细胞凋亡以及对白细胞介素（IL）-5所致嗜酸性粒细胞存活的影响。还评估了c-Jun氨基末端激酶（JNK）在介导抗组胺药对嗜酸性粒细胞凋亡作用中的作用。通过测量碘化丙啶染色细胞的相对DNA含量评估分离的人嗜酸性粒细胞的凋亡，并通过形态学分析进行确认。通过蛋白质印迹法测量JNK的活性。发现抗组胺药通过增强凋亡来逆转IL-5对嗜酸性粒细胞的存活延长作用。发现JNK在苯海拉明诱导的嗜酸性粒细胞凋亡过程中缓慢激活。一种对JNK特异的抑制肽L-JNKI1（JNK肽抑制剂1，L-立体异构体）抑制苯海拉明介导的嗜酸性粒细胞凋亡。我们的结果表明，第一代抗组胺药苯海拉明和氯苯那敏可逆转IL-5所致的嗜酸性粒细胞存活，且抗组胺药增强的凋亡是通过JNK的激活介导的。因此，逆转IL-5所致的嗜酸性粒细胞存活可能有助于苯海拉明和氯苯那敏的抗过敏作用。
