Adenosine promotes Foxp3 expression in Treg cells in sepsis model by activating JNK/AP-1 pathway

作者：Bao Rui; Hou Jiong; Li Yan; Bian Jinjun; Deng Xiaoming; Zhu Xiaoyan^*; Yang Tao^*

来源：American Journal of Translational Research, 2016, 8(5): 2284-2292.

• Sepsis
• adenosine
• Foxp3
• JNK/AP-1 pathway
• regulatory T cells

Objectives: Forkhead/winged helix transcription factor p3 (Foxp3) increases in CD4(+)CD25(+)Treg cells during sepsis; however, related mechanisms are unclear. Our study aimed to explore the possible molecular mechanisms of high expression of Foxp3 in Treg cells during sepsis. Methods: Sepsis was induced by cecal ligation and puncture (CLP) method. CD4(+)CD25(+) Treg cells were isolated from peripheral blood and identified by flow cytometry (FCM). Treg cells were cultured with or without adenosine, adenosine agonist, adenosine antagonist, SMAD family member 3 (Smad3) agonist (transforming growth factor (TGF)-beta 1), or C-Jun N-Terminal Kinase (JNK) inhibitor. Expression levels of Foxp3 and activator protein 1 (AP-1) were determined. The binding of c-Fos or c-Jun to the Foxp3 promoter was then evaluated by the chromatin immunoprecipitation (ChIP) assay and quantified by quantitative real-time PCR (qRT-PCR). The mRNA and protein levels of Foxp3 were determined after transfection with siRNA against c-Fos, Fra2, c-Jun or JunD. Results: Pharmacological inhibition of both adenosine and JNK reduced Foxp3 protein levels. JNK/AP-1 activation was involved in increased levels of Foxp3 protein in CD4(+)CD25(+) Treg cells. AP-1 regulated activity of Foxp3 promoter in Treg cells, and the induction of c-Fos or c-Jun activity leads to elevated transcription of Foxp3 gene. Knockdown of c-Fos, Fra-2, c-Jun, or JunD levels also reduced Foxp3 expression. Conclusion: We confirm that adenosine plays significant roles in the high expression of Foxp3. Adenosine promotes Foxp3 expression in Treg cells during sepsis via JNK/AP-1 pathway.

• 出版日期2016
• 单位中国人民解放军第二军医大学