Allergic diseases, which affect up to 20-30% of the world population, are still therapeutic challenge for allergists. Tetracyclines, which belong to an antibiotic drug family that possesses a striking variety of non-antibiotic properties, have been successfully applied to a wide range of diseases. However, their roles in allergic conjunctivitis and anaphylaxis and their underlying anti-allergy mechanisms remain elusive. Here, we reported that treatment with doxycycline significantly reduced IgE release from mouse B cells and the degranulation and inflammatory cytokines production of mouse mast cells (MCs) activated by IgE-dependent way. Furthermore, doxycycline treatment significantly inhibited histamine-induced vascular hyperpermeability in vitro. Mechanistically, the doxycycline-mediated inhibition of B cells, MCs and histamine may occur via modulation of the PI3K/Akt pathway. In vivo, our results demonstrated that treatment with doxycycline significantly attenuated clinical symptoms of mouse models of experimental allergic conjunctivitis (EAC) with a significant decrease in inflammatory cell frequency, IgE production, histamine release, and a decrease in TNF-α and IL-4 production. Using mouse models of MCs-dependent passive systemic anaphylaxis (PSA), we further confirmed anti-allergy effects of doxycycline and doxycycline-mediated inhibitory effects on MCs. Furthermore, our results showed that doxycycline significantly attenuate histamine-induced systemic anaphylaxis-like reaction (HISA) with a significantly downregulation of PI3K/Akt/eNOS/VE-cadherin pathway. The doxycycline-mediated anti-allergy effects during EAC, PSA and HISA were abrogated when an Akt activator, SC79, was administered. These findings suggest that doxycycline inhibits B cell, MC and histamine function and attenuates experimental allergic conjunctivitis and systemic anaphylaxis by possible modulating the PI3K/Akt pathway.

译文

过敏性疾病影响着全球20%至30%的人口,仍然是过敏症患者的治疗挑战。四环素属于一种抗生素药物家族,具有惊人的多种非抗生素特性,已成功应用于多种疾病。然而,它们在过敏性结膜炎和过敏反应中的作用及其潜在的抗过敏机制仍然难以捉摸。在这里,我们报道用强力霉素进行治疗可显着降低小鼠B细胞释放的IgE以及通过IgE依赖性方式激活的小鼠肥大细胞(MC)的脱颗粒和炎性细胞因子的产生。此外,强力霉素在体外可显着抑制组胺诱导的血管通透性过高。从机理上讲,强力霉素介导的对B细胞,MC和组胺的抑制作用可能是通过PI3K / Akt途径的调节而发生的。在体内,我们的结果表明,用强力霉素进行治疗可显着减轻实验性变应性结膜炎(EAC)小鼠模型的临床症状,炎症细胞频率,IgE产生,组胺释放以及TNF-α和IL-4的降低均显着降低生产。使用小鼠模型的MCs依赖的被动系统性过敏反应(PSA),我们进一步证实了强力霉素的抗过敏作用和强力霉素对MCs介导的抑制作用。此外,我们的结果表明,强力霉素显着减弱了PI3K / Akt / eNOS / VE-钙粘蛋白途径的组织胺诱导的全身过敏样反应(HISA)。当使用Akt激活剂SC79时,EAC,PSA和HISA中强力霉素介导的抗过敏作用被取消。这些发现表明强力霉素可通过调节PI3K / Akt途径来抑制B细胞,MC和组胺功能,并减轻实验性过敏性结膜炎和全身性过敏反应。

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