Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH OH 44106, USA.
Immunology. 2012 Feb;135(2):140-50. doi: 10.1111/j.1365-2567.2011.03519.x.
Regulation of inducible nitric oxide synthase (NOS2) expression is important given the role of this enzyme in inflammation, control of infections and immune regulation. In contrast to tumour necrosis factor-α (TNF-α) alone or CD40 stimulation alone, simultaneous stimulation of mouse macrophages through CD40 ligation and TNF-α led to up-regulation of NOS2 and nitric oxide production. This response was of functional relevance because CD40/TNF-α-stimulated macrophages acquired nitric oxide-dependent anti-Leishmania major activity. CD40 plus TNF-α up-regulated NOS2 independently of interferon-γ, interferon-α/β and interleukin-1. TNF receptor-associated factor 6 (TRAF6), an adapter protein downstream of CD40, appears to be required for NOS2 up-regulation because a CD40-TRAF6 blocking peptide inhibited up-regulation of NOS2 in CD40/TNF-α-stimulated macrophages. CCAAT/enhancer-binding protein-β (C/EBPβ), a transcription factor activated by TNF-α but not CD40, was required for NOS2 up-regulation because this enzyme was not up-regulated when C/EBPβ(-/-) macrophages received CD40 plus TNF-α stimulation. These results indicate that CD40 and TNF-α co-operate to up-regulate NOS2, probably via the effect of TRAF6 and C/EBPβ.
诱导型一氧化氮合酶（NOS2）表达的调控非常重要，因为这种酶在炎症、感染控制和免疫调节中发挥作用。与单独的肿瘤坏死因子-α（TNF-α）或单独的 CD40 刺激相比，通过 CD40 交联和 TNF-α 同时刺激小鼠巨噬细胞会导致 NOS2 的上调和一氧化氮的产生。这种反应具有功能相关性，因为 CD40/TNF-α 刺激的巨噬细胞获得了依赖于一氧化氮的抗利什曼原虫主要活性。CD40 加 TNF-α 上调 NOS2 不依赖于干扰素-γ、干扰素-α/β 和白细胞介素-1。CD40 下游的衔接蛋白 TNF 受体相关因子 6（TRAF6）似乎是 NOS2 上调所必需的，因为 CD40/TRAF6 阻断肽抑制了 CD40/TNF-α 刺激的巨噬细胞中 NOS2 的上调。CCAAT/增强子结合蛋白-β（C/EBPβ）是一种被 TNF-α激活但不被 CD40 激活的转录因子，它是 NOS2 上调所必需的，因为当 C/EBPβ(-/-)巨噬细胞接受 CD40 加 TNF-α刺激时，这种酶不会上调。这些结果表明，CD40 和 TNF-α 合作上调 NOS2，可能通过 TRAF6 和 C/EBPβ 的作用。
