Tendler D S, Bao C, Wang T, Huang E L, Ratovitski E A, Pardoll D A, Lowenstein C J
Division of Cardiology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Cancer Res. 2001 May 1;61(9):3682-8.
Activated macrophages play a central role in antitumor immunity. However, the stimuli that activate macrophages to kill tumor cells are not completely understood. Because the center of solid tumors can be hypoxic, we hypothesized that hypoxia may be an important signal in activating macrophages to kill tumor cells. Hypoxia stimulates IFN-primed macrophages to express the inducible nitric oxide synthase (NOS2) and to synthesize nitric oxide (NO). We show that this synergy between IFN and hypoxia is mediated by the direct interaction of the hypoxia inducible factor-1 (HIF-1) and IFN regulatory factor-1 (IRF-1), which are both required for the hypoxic transcription of NOS2. This interaction between HIF-1 and IRF-1 may explain the mechanism by which macrophages infiltrating into tumors are activated to express NOS2 and to produce NO, a mediator of tumor apoptosis.
活化的巨噬细胞在抗肿瘤免疫中发挥核心作用。然而，激活巨噬细胞以杀伤肿瘤细胞的刺激因素尚未完全明确。由于实体瘤中心可能处于缺氧状态，我们推测缺氧可能是激活巨噬细胞杀伤肿瘤细胞的重要信号。缺氧刺激经干扰素（IFN）预处理的巨噬细胞表达诱导型一氧化氮合酶（NOS2）并合成一氧化氮（NO）。我们发现，IFN与缺氧之间的这种协同作用是由缺氧诱导因子-1（HIF-1）和IFN调节因子-1（IRF-1）的直接相互作用介导的，这两者都是NOS2缺氧转录所必需的。HIF-1与IRF-1之间的这种相互作用可能解释了浸润到肿瘤中的巨噬细胞被激活以表达NOS2并产生NO（一种肿瘤凋亡介质）的机制。
