期刊
IMMUNITY
卷 30, 期 3, 页码 372-383出版社
CELL PRESS
DOI: 10.1016/j.immuni.2008.12.021
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- National Institute of Biomedical Innovation (NIBIO)
- Astellas Foundation for Research on Metabolic Disorders
- Japan Intractable Disease Research Foundation
- Mochica Memorial Foundation
- Naito Memorial Foundation
- Princess Takamatsu Cancer Research Fund
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.
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