Ray Neelanjan, Kuwahara Masayoshi, Takada Yasunari, Maruyama Kenta, Kawaguchi Tomohiro, Tsubone Hirokazu, Ishikawa Hiromichi, Matsuo Koichi
Department of Microbiology and Immunology, School of Medicine, Keio University, 35 Shinanomachi, 160-8582 Tokyo, Japan.
Int Immunol. 2006 May;18(5):671-7. doi: 10.1093/intimm/dxl004. Epub 2006 Mar 28.
We explored the role of the transcription factor c-Fos in lipopolysaccharide (LPS)-induced cytokine response using mice lacking c-Fos (Fos-/- mice). Compared with wild-type controls, Fos-/- macrophages and mice showed significantly enhanced production of tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12 p40, but reduced production of the anti-inflammatory cytokine IL-10. Bandshift analysis revealed that LPS-induced NF-kappaB binding activity to a functional site in the TNF-alpha promoter was significantly higher in Fos-/- than in wild-type macrophages. Using telemetry, we monitored body temperature and heart rate after LPS injection and found that Fos-/- mice undergo more severe hypothermia and bradycardia than wild-type mice. Such shock responses in Fos-/- mice were significantly reversed by neutralizing TNF-alpha. These data reveal a novel in vivo role for c-Fos as an anti-inflammatory transcription factor acting through suppression of NF-kappaB activity.
我们利用缺乏c-Fos的小鼠（Fos-/-小鼠）探究了转录因子c-Fos在脂多糖（LPS）诱导的细胞因子反应中的作用。与野生型对照相比，Fos-/-巨噬细胞和小鼠表现出肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6和IL-12 p40的产生显著增强，但抗炎细胞因子IL-10的产生减少。凝胶迁移分析显示，LPS诱导的NF-κB与TNF-α启动子功能位点的结合活性在Fos-/-巨噬细胞中显著高于野生型巨噬细胞。通过遥测技术，我们监测了LPS注射后的体温和心率，发现Fos-/-小鼠比野生型小鼠经历更严重的体温过低和心动过缓。Fos-/-小鼠中的这种休克反应通过中和TNF-α得到显著逆转。这些数据揭示了c-Fos作为一种通过抑制NF-κB活性发挥作用的抗炎转录因子在体内的新作用。
