title: Adenine suppresses IgE-mediated mast cell activation.
abstract: Nucleobase adenine is produced by dividing human lymphoblasts mainly from polyamine synthesis and inhibits immunological functions of lymphocytes. We investigated the anti-allergic effect of adenine on IgE-mediated mast cell activation in vitro and passive cutaneous anaphylaxis (PCA) in mice. Intraperitoneal injection of adenine to IgE-sensitized mice attenuated IgE-mediated PCA reaction in a dose dependent manner, resulting in a median effective concentration of 4.21 mg/kg. In mast cell cultures, only adenine among cytosine, adenine, adenosine, ADP and ATP dose-dependently suppressed FcɛRI (a high affinity receptor for IgE)-mediated degranulation with a median inhibitory concentration of 1.6mM. It also blocked the production of LTB4, an inflammatory lipid mediator, and inflammatory cytokines TNF-α and IL-4. In addition, adenine blocked thapsigargin-induced degranulation which is FcɛRI-independent but shares FcɛRI-dependent signaling events. Adenine inhibited the phosphorylation of signaling molecules important to FcɛRI-mediated allergic reactions such as Syk, PLCγ2, Gab2, Akt, and mitogen activated protein kinases ERK and JNK. From this result, we report for the first time that adenine inhibits PCA in mice and allergic reaction by inhibiting FcɛRI-mediated signaling events in mast cells. Therefore, adenine may be useful for the treatment of mast cell-mediated allergic diseases. Also, the upregulation of adenine production may provide another mechanism for suppressing mast cell activity especially at inflammatory sites.
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Prashanta
authors.initials: P
authors.lastname: Silwal
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Keuna
authors.initials: K
authors.lastname: Shin
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Seulgi
authors.initials: S
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Seong Wook
authors.initials: SW
authors.lastname: Kang
authors.affiliation: Department of Physiology, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Jin Bong
authors.initials: JB
authors.lastname: Park
authors.affiliation: Department of Physiology, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Hyang-Joo
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Moghu Research Center Ltd., BVC #311, KRICT, Yuseong, Daejeon 305-333, Republic of Korea.
authors.forename: Suk-Jin
authors.initials: SJ
authors.lastname: Koo
authors.affiliation: Moghu Research Center Ltd., BVC #311, KRICT, Yuseong, Daejeon 305-333, Republic of Korea.
authors.forename: Kun-Hoe
authors.initials: KH
authors.lastname: Chung
authors.affiliation: Department of Oriental Medicine, Daejeon University, Daejeon 300-716, Republic of Korea.
authors.forename: Uk
authors.initials: U
authors.lastname: Namgung
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Kyu
authors.initials: K
authors.lastname: Lim
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Jun-Young
authors.initials: JY
authors.lastname: Heo
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
authors.forename: Jong Il
authors.initials: JI
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea; Research Institute for Medical Sciences, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea. Electronic address: parksk@cnu.ac.kr.
authors.forename: Seung-Kiel
authors.initials: SK
authors.lastname: Park
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000225:Adenine / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000707:Anaphylaxis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007073:Immunoglobulin E / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology; D007975:Leukotriene B4 / Q000276:immunology; D008407:Mast Cells / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D051966:Phospholipase C gamma / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000276:immunology; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D017455:Receptors, IgE / Q000276:immunology; D000072377:Syk Kinase; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490894:Gab2 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017455:Receptors, IgE; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D015847:Interleukin-4; D007073:Immunoglobulin E; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D051966:Phospholipase C gamma; D000225:Adenine
keywords: Adenine; Degranulation; IgE; Mast cell; Passive cutaneous anaphylaxis (PCA)