Institute of Experimental Medicine, Academy of Sciences, Vídeňská 1083, 14220 Prague 4, Czech Republic.
Int Immunopharmacol. 2012 Feb;12(2):342-9. doi: 10.1016/j.intimp.2011.12.005. Epub 2011 Dec 21.
Acyclic nucleoside phosphonates (ANP) are virostatics effective against viruses like hepatitis B virus and human immunodeficiency virus. Our previous reports indicated immunomodulatory activities of ANP in mouse and human innate immune cells. Recently, evidence has increased that hepatocytes may play an active role in immune regulation of the liver homeostasis or injury. In this study we investigated possible immunomodulatory effects of ANP on rat hepatocytes and macrophages. Nitric oxide (NO) production and secretion of cytokines (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-13, IL-18, IFN-γ, TNF-α and GM-CSF) were analyzed under in vitro conditions. Test compounds included: 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; adefovir); 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP); (R)- and (S)-enantiomers of 9-[2-(phosphonomethoxy)propyl]adenine [(R)-PMPA; tenofovir] and [(S)-PMPA]; 9-[2-(phosphonomethoxy)propyl]-2,6-diaminopurine [(R)-PMPDAP] and [(S)-PMPDAP]. The group of test compounds also included their N(6)-substituted derivatives. Some of ANP which are able to induce NO production and cytokine secretion in cultured macrophages possess the same immunobiological activity in isolated hepatocytes. The extent of responses is in range of LPS/IFN-γ stimulation in both types of cells. The effects of active ANP on NO expression and cytokine secretion are dose- and time-dependent. Interestingly, the spectrum of detected cytokines induced by ANP is broader in hepatocytes. The results also confirm immunomodulatory effects of some ANP on rodent macrophages. Moreover, we demonstrate for the first time immunobiological reactivity of primary rat hepatocytes induced by exogenous ANP compounds. The potential of hepatocytes to synthesize cytokines can contribute to better understanding of liver immune function and can serve for pharmacological intervention in liver diseases.
无环核苷膦酸（ANP）是一种针对乙型肝炎病毒和人类免疫缺陷病毒等病毒的抗病毒药物。我们之前的报告表明，ANP 在小鼠和人类先天免疫细胞中具有免疫调节活性。最近，越来越多的证据表明肝细胞可能在肝脏稳态或损伤的免疫调节中发挥积极作用。在这项研究中，我们研究了 ANP 对大鼠肝细胞和巨噬细胞可能产生的免疫调节作用。在体外条件下分析了一氧化氮（NO）的产生和细胞因子（IL-1α、IL-1β、IL-2、IL-4、IL-6、IL-10、IL-13、IL-18、IFN-γ、TNF-α 和 GM-CSF）的分泌。测试化合物包括：9-[2-（膦酸甲氧基）乙基]腺嘌呤（PMEA；阿德福韦）；9-[2-（膦酸甲氧基）乙基]-2,6-二氨基嘌呤（PMEDAP）；（R）-和（S）-9-[2-（膦酸甲氧基）丙基]腺嘌呤[（R）-PMPA；替诺福韦]和[（S）-PMPA]；9-[2-（膦酸甲氧基）丙基]-2,6-二氨基嘌呤[（R）-PMPDAP]和[（S）-PMPDAP]。测试化合物组还包括它们的 N（6）取代衍生物。一些能够诱导培养的巨噬细胞产生 NO 产生和细胞因子分泌的 ANP 在分离的肝细胞中具有相同的免疫生物学活性。两种细胞中，反应的程度在 LPS/IFN-γ 刺激范围内。活性 ANP 对 NO 表达和细胞因子分泌的影响具有剂量和时间依赖性。有趣的是，ANP 诱导的检测到的细胞因子谱在肝细胞中更为广泛。结果还证实了一些 ANP 对啮齿动物巨噬细胞的免疫调节作用。此外，我们首次证明了外源性 ANP 化合物诱导原代大鼠肝细胞产生免疫生物学反应。肝细胞合成细胞因子的潜力有助于更好地理解肝脏免疫功能，并可用于肝脏疾病的药理学干预。
