title: Doxycycline exerts multiple anti-allergy effects to attenuate murine allergic conjunctivitis and systemic anaphylaxis.
abstract: 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.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Clinic Immunology Section, Sun Yat-sen University Third Affiliated Hospital, Guangzhou, China.
authors.forename: Wenru
authors.initials: W
authors.lastname: Su
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Longhui
authors.initials: L
authors.lastname: Han
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, USA.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Chen
authors.affiliation: Clinic Immunology Section, Sun Yat-sen University Third Affiliated Hospital, Guangzhou, China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Chen
authors.affiliation: Clinic Immunology Section, Sun Yat-sen University Third Affiliated Hospital, Guangzhou, China; Division of Rheumatology, Department of Medicine, Penn State University Hershey College of Medicine, USA. Electronic address: szheng1@hmc.psu.edu.
authors.forename: Song Guo
authors.initials: SG
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China. Electronic address: liangd2@mail.sysu.edu.cn.
authors.forename: Dan
authors.initials: D
authors.lastname: Liang
mesh_terms: D000707:Anaphylaxis / Q000517:prevention & control*; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D003233:Conjunctivitis, Allergic / Q000188:drug therapy*; D004318:Doxycycline / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology; D007073:Immunoglobulin E / Q000378:metabolism; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D018926:Anti-Allergic Agents; D015703:Antigens, CD; D015820:Cadherins; D004318:Doxycycline; D006633:Histamine Antagonists; D007073:Immunoglobulin E; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099152:Cadherin 5; C496315:Nos3 protein, mouse
keywords: Allergy; B cells; Doxycycline; Histamine; Mast cells