Choe So-Hui, Choi Eun-Young, Hyeon Jin-Yi, Choi In Soon, Kim Sung-Jo
Department of Biological Science, College of Medical and Life Sciences, Silla University, Busan, South Korea.
Department of Periodontology, School of Dentistry, Pusan National University, Yangsan, Gyeongsangnam-do, South Korea; Dental Research Institute, Pusan National University Dental Hospital, Yangsan, Gyeongsangnam-do, South Korea; Institute of Translational Dental Sciences, Pusan National University, Yangsan, Gyeongsangnam-do, South Korea.
Biochem Biophys Res Commun. 2017 Oct 14;492(2):224-230. doi: 10.1016/j.bbrc.2017.08.055. Epub 2017 Aug 16.
The purpose of this study was to investigate the influences of NCX 2121, a nitric oxide (NO)-releasing derivative of indomethacin, upon the generation of proinflammatory mediators using murine macrophages activated by lipopolysaccharide (LPS) isolated from Prevotella intermedia, which is one of the pathogens implicated in periodontal diseases. Inducible NO synthase (iNOS)-derived NO, IL-1β and IL-6 as well as their relevant mRNA were significantly attenuated by NCX 2121 in RAW264.7 cells activated by P. intermedia LPS. NCX 2121 was much more effective than the parental compound indomethacin in reducing these proinflammatory mediators. NCX 2121 triggered induction of heme oxygenase-1 (HO-1) in cells exposed to P. intermedia LPS, and its inhibitory influence upon P. intermedia LPS-elicited NO generation was notably blocked by SnPP treatment. NCX 2121 attenuated NF-κB-dependent SEAP release induced by P. intermedia LPS. NCX 2121 did not display inhibitory action towards IκB-α degradation triggered by LPS. Instead, it significantly diminished nuclear translocation as well as DNA-binding action of NF-κB p50 subunit elicited by P. intermedia LPS. Further, NCX 2121 significantly up-regulated SOCS1 mRNA expression in cells challenged with P. intermedia LPS. In summary, NCX 2121 down-regulates P. intermedia LPS-elicited generation of NO, IL-1β and IL-6 in murine macrophages in a mechanism that involves anti-inflammatory HO-1 induction as well as decrement of NF-κB activation, which may be associated with SOCS1 expression. NCX 2121 may have potential benefits as a host immunomodulatory agent for the therapy of periodontal disease.
本研究的目的是调查吲哚美辛的一氧化氮（NO）释放衍生物NCX 2121对使用由牙龈卟啉单胞菌分离的脂多糖（LPS）激活的小鼠巨噬细胞产生促炎介质的影响，牙龈卟啉单胞菌是涉及牙周疾病的病原体之一。在由牙龈卟啉单胞菌LPS激活的RAW264.7细胞中，NCX 2121显著减弱了诱导型一氧化氮合酶（iNOS）衍生的NO、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）及其相关mRNA。在减少这些促炎介质方面，NCX 2121比母体化合物吲哚美辛更有效。NCX 2121在暴露于牙龈卟啉单胞菌LPS的细胞中触发了血红素加氧酶-1（HO-1）的诱导，并且其对牙龈卟啉单胞菌LPS诱导的NO生成的抑制作用被锡原卟啉（SnPP）处理显著阻断。NCX 2121减弱了牙龈卟啉单胞菌LPS诱导的NF-κB依赖性分泌型碱性磷酸酶（SEAP）释放。NCX 2121对LPS触发的IκB-α降解没有显示出抑制作用。相反，它显著减少了牙龈卟啉单胞菌LPS引起的NF-κB p50亚基的核转位以及DNA结合作用。此外，NCX 2121在受到牙龈卟啉单胞菌LPS攻击的细胞中显著上调了细胞因子信号转导抑制因子1（SOCS1）mRNA表达。总之，NCX 2121通过涉及抗炎性HO-1诱导以及NF-κB激活减少的机制下调牙龈卟啉单胞菌LPS诱导的小鼠巨噬细胞中NO、IL-1β和IL-6的生成，这可能与SOCS1表达有关。NCX 2121作为一种宿主免疫调节剂用于牙周疾病的治疗可能具有潜在益处。
