Silwal Prashanta, Shin Keuna, Choi Seulgi, Kang Seong Wook, Park Jin Bong, Lee Hyang-Joo, Koo Suk-Jin, Chung Kun-Hoe, Namgung Uk, Lim Kyu, Heo Jun-Young, Park Jong Il, Park Seung-Kiel
Department of Biochemistry, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 301-747, Republic of Korea.
Mol Immunol. 2015 Jun;65(2):242-9. doi: 10.1016/j.molimm.2015.01.021. Epub 2015 Feb 17.
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.
核碱基腺嘌呤主要由人类淋巴母细胞通过多胺合成产生，并抑制淋巴细胞的免疫功能。我们研究了腺嘌呤在体外对IgE介导的肥大细胞活化以及在小鼠被动皮肤过敏反应（PCA）中的抗过敏作用。向IgE致敏小鼠腹腔注射腺嘌呤以剂量依赖的方式减弱了IgE介导的PCA反应，中位有效浓度为4.21mg/kg。在肥大细胞培养物中，胞嘧啶、腺嘌呤、腺苷、ADP和ATP中只有腺嘌呤以剂量依赖的方式抑制FcɛRI（IgE的高亲和力受体）介导的脱颗粒，中位抑制浓度为1.6mM。它还阻断了炎症脂质介质LTB4以及炎症细胞因子TNF-α和IL-4的产生。此外，腺嘌呤阻断了毒胡萝卜素诱导的脱颗粒，该脱颗粒不依赖FcɛRI，但与FcɛRI依赖性信号事件有共同之处。腺嘌呤抑制了对FcɛRI介导的过敏反应重要的信号分子的磷酸化，如Syk、PLCγ2、Gab2、Akt以及丝裂原活化蛋白激酶ERK和JNK。基于此结果，我们首次报道腺嘌呤通过抑制肥大细胞中FcɛRI介导的信号事件来抑制小鼠的PCA和过敏反应。因此，腺嘌呤可能对治疗肥大细胞介导的过敏性疾病有用。此外，腺嘌呤产生的上调可能为抑制肥大细胞活性提供另一种机制，尤其是在炎症部位。
