Denlinger L C, Fisette P L, Garis K A, Kwon G, Vazquez-Torres A, Simon A D, Nguyen B, Proctor R A, Bertics P J, Corbett J A
MD/PhD Program, University of Wisconsin Medical School, Madison 53706, USA.
J Biol Chem. 1996 Jan 5;271(1):337-42. doi: 10.1074/jbc.271.1.337.
Macrophage activation is central to the progression of multiple diseases via the release of inflammatory mediators such as cytokines and nitric oxide. Despite the recognized overlap in the regulatory mechanisms involved in mediator production, little formation exists regarding receptor-initiated signaling pathways that coordinately control multiple end points, such as tumor necrosis factor-alpha (TNF-alpha) and nitric oxide production. In this study, the expression of inducible nitric oxide synthase (iNOS) in macrophages is shown to be regulated by calcium and by a purinoreceptor signaling system. The P2Y purinoreceptor partial agonist, 2-methylthio-ATP (2-MeS-ATP), inhibits the expression of iNOS induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) in primary macrophages. Additionally, 2-MeS-ATP attenuates the expression of iNOS in macrophages isolated from CD-1 mice challenged with LPS, and it inhibits LPS-induced TNF-alpha and interleukin-1 alpha (IL-1 alpha) release, thereby preventing endotoxic death. Thus, purinoreceptors and calcium are likely to be critical for macrophage activation and the production of inflammatory mediators stimulated by LPS.
巨噬细胞的激活通过释放细胞因子和一氧化氮等炎症介质，在多种疾病的进展中起着核心作用。尽管已知参与介质产生的调节机制存在重叠，但关于协调控制多个终点（如肿瘤坏死因子-α（TNF-α）和一氧化氮产生）的受体启动信号通路的信息却很少。在本研究中，巨噬细胞中诱导型一氧化氮合酶（iNOS）的表达显示受钙和嘌呤受体信号系统调节。P2Y嘌呤受体部分激动剂2-甲基硫代三磷酸腺苷（2-MeS-ATP）可抑制原代巨噬细胞中脂多糖（LPS）加干扰素-γ（IFN-γ）诱导的iNOS表达。此外，2-MeS-ATP可减弱从经LPS攻击的CD-1小鼠分离出的巨噬细胞中iNOS的表达，并抑制LPS诱导的TNF-α和白细胞介素-1α（IL-1α）释放，从而防止内毒素性死亡。因此，嘌呤受体和钙可能对巨噬细胞激活以及LPS刺激的炎症介质产生至关重要。
