Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo.
Forced expression of stabilized c-Fos in dendritic cells reduces cytokine production and immune responses in vivo.
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DOI：
10.1016/j.bbrc.2012.05.097
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发表时间：
2012-06
影响因子：
3.1
通讯作者：
Ryoko Yoshida;Mayu Suzuki;Ryota Sakaguchi;Eiichi Hasegawa;A. Kimura;T. Shichita;T. Sekiya;H. Shiraishi;K. Shimoda;A. Yoshimura
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文献类型：
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作者：
Ryoko Yoshida;Mayu Suzuki;Ryota Sakaguchi;Eiichi Hasegawa;A. Kimura;T. Shichita;T. Sekiya;H. Shiraishi;K. Shimoda;A. Yoshimura
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。我们已经证明，转录因子c-Fos负责cAMP介导的炎症细胞因子产生的抑制，并且c-Fos蛋白通过IKK β介导的磷酸化而稳定。我们发现S308是主要的磷酸化位点之一，并且S308D突变使c-Fos半衰期延长。为了研究稳定的c-Fos蛋白在体内树突状细胞（DCs）中的作用，我们产生了CD11c启动子衍生的c-FosS308D转基因小鼠。正如预期的那样，与野生型（Wt）小鼠相比，这些Tg小鼠的骨髓来源的DC（BMDC）产生更少量的炎症细胞因子，包括TNF-α，IL-12和IL-23，但IL-10水平更高。当T细胞与来自Tg小鼠的BMDC共培养时，Th1和Th17细胞因子的产生减少，但T细胞增殖不受影响。Tg小鼠表现出更多的抵抗实验性自身免疫性脑脊髓炎（EAE）比野生型小鼠。这些数据表明，在DC中的c-Fos在某些先天性和适应性免疫应答中起抑制作用。
Intracellular cyclic adenosine monophosphate (cAMP) suppresses innate immunity by inhibiting proinflammatory cytokine production by monocytic cells. We have shown that the transcription factor c-Fos is responsible for cAMP-mediated suppression of inflammatory cytokine production, and that c-Fos protein is stabilized by IKKβ-mediated phosphorylation. We found that S308 is one of the major phosphorylation sites, and that the S308D mutation prolongs c-Fos halflife. To investigate the role of stabilized c-Fos protein in dendritic cells (DCs) in vivo, we generated CD11c-promoter-deriven c-FosS308D transgenic mice. As expected, bone marrow-derived DCs (BMDCs) from these Tg mice produced smaller amounts of inflammatory cytokines, including TNF-α, IL-12, and IL-23, but higher levels of IL-10, in response to LPS, than those from wild-type (Wt) mice. When T cells were co-cultured with BMDCs from Tg mice, production of Th1 and Th17 cytokines was reduced, although T cell proliferation was not affected. Tg mice demonstrated more resistance to experimental autoimmune encephalomyelitis (EAE) than did Wt mice. These data suggest that c-Fos in DCs plays a suppressive role in certain innate and adaptive immune responses.