Interleukin-10-positive (IL-10(+)) regulatory B (Breg) cells play an important role in restraining excessive inflammatory responses by secreting IL-10. However, it is still unclear what key transcription factors determine Breg cell differentiation. Hence, we explore what transcription factor plays a key role in the expression of IL-10, a pivotal cytokine in Breg cells. We used two types of web-based prediction software to predict transcription factors binding the IL-10 promoter and found that IL-10 promoter had many binding sites for Foxd3. Chromatin immunoprecipitation PCR assay demonstrated that Foxd3 directly binds the predicted binding sites around the start codon upstream by -1400 bp. Further, we found that Foxd3 suppressed the activation of IL-10 promoter by using an IL-10 promoter report system. Finally, knocking out Foxd3 effectively promotes Breg cell production by up-regulating IL-10 expression. Conversely, up-regulated Foxd3 expression was negatively associated with IL-10(+) Breg cells in lupus-prone MRL/lpr mice. Hence, our data suggest that Foxd3 suppresses the production of IL-10(+) Breg cells by directly binding the IL-10 promoter. This study demonstrates the mechanism for Breg cell production and its application to the treatment of autoimmune diseases by regulating Foxd3 expression.
[1]Henan Univ, Coll Pharm, Kaifeng 475004, Peoples R China.
[2]Inst Basic Med Sci, Immunol Lab, POB 130 3,Taiping Rd 27, Beijing, Peoples R China.
[3]Jilin Univ, Dept Biomed, Inst Frontier Med Sci, Sch Pharmaceut Sci, Changchun, Peoples R China.
[4]307th Hosp Chinese Peoples Liberat Army, Dept Nephrol, Beijing, Peoples R China.
[5]Henan Univ, Lab Cellular & Mol Immunol, Kaifeng, Henan, Peoples R China.
[6]Jilin Univ, Dept Rheumatol, Hosp 1, Changchun, Peoples R China.
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