Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein
Cyclic Adenosine Monophosphate Suppresses the Transcription of Proinflammatory Cytokines via the Phosphorylated c-Fos Protein
复制标题
DOI：
10.1016/j.immuni.2008.12.021
复制
发表时间：
2009-03-20
期刊：
影响因子：
32.4
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Koga, Keiko;Takaesu, Giichi;Yoshimura, Akihiko
细胞内环磷酸腺苷（cAMP）通过抑制单核细胞产生促炎细胞因子来抑制先天性免疫。白细胞介素-10（IL-10）的表达增强被认为是抑制的机制。然而，cAMP仍然能够抑制IL-10缺陷型树突状细胞（DC）中细胞因子TINIF-a和IL-12的产生。在这里，我们证明了转录因子c-Fos负责cAMP介导的抑制炎症细胞因子的产生。c-Fos在cAMP和脂多糖（LIPS）的作用下大量积累。c-Fos的过表达抑制LPS诱导的细胞因子产生，而cAMP介导的TNF-α和IL-12的抑制在Fos（-/-）DC或用c-Fos SiRNA处理的RAW 264.7细胞中受损。c-Fos与p65蛋白发生物理相互作用，并减少p65向Tnf启动子的募集。c-Fos的多个位点被IKK β蛋白磷酸化。因此，我们认为c-Fos是IKK β的底物，并负责cAMP的免疫抑制作用。
Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production from monocytic cells. Enhanced expression of interleukin-10 (IL-10) has been suggested to be the mechanism of suppression. However, cAMP is still capable of suppressing production of the cytokines; TINIF-alpha and IL-12 in IL-10-deficient dendritic cells (DCs). Here, we demonstrated that the transcription factor c-Fos was responsible for the cAMP-mediated suppression of inflammatory cytokine production. c-Fos accumulated at high amounts in response to cAMP and lipopolysaccharide (LIPS). Overexpression of c-Fos suppressed LPS-induced cytokine production, whereas cAMP-mediated suppression of TNF-alpha and IL-12 was impaired in Fos(-/-) DCs or in RAW264.7 cells treated with c-Fos SiRNA. c-Fos physically interacted with p65 protein and reduced the recruitment of p65 to the Tnf promoter. Multiple sites of c-Fos were phosphorylated by the IKK beta protein. Thus, we propose that c-Fos is a substrate of IKK beta and is responsible for the immunosuppressive effect of cAMP.