論文 - 詳細
| RRC ID | 43455 |
|---|---|
| 著者 | Tsuji-Takayama K, Suzuki M, Yamamoto M, Harashima A, Okochi A, Otani T, Inoue T, Sugimoto A, Toraya T, Takeuchi M, Yamasaki F, Nakamura S, Kibata M. |
| タイトル | The production of IL-10 by human regulatory T cells is enhanced by IL-2 through a STAT5-responsive intronic enhancer in the IL-10 locus. |
| ジャーナル | J Immunol |
| Abstract |
STAT5 molecules are key components of the IL-2 signaling pathway, the deficiency of which often results in autoimmune pathology due to a reduced number of CD4(+)CD25(+) naturally occurring regulatory T (Treg) cells. One of the consequences of the IL-2-STAT5 signaling axis is up-regulation of FOXP3, a master control gene for naturally occurring Treg cells. However, the roles of STAT5 in other Treg subsets have not yet been elucidated. We recently demonstrated that IL-2 enhanced IL-10 production through STAT5 activation. This occurred in two types of human Treg cells: a novel type of umbilical cord blood-derived Treg cell, termed HOZOT, and Tr1-like Treg cells, IL-10-Treg. In this study, we examined the regulatory mechanisms of IL-10 production in these Treg cells, focusing specifically on the roles of STAT5. By performing bioinformatic analysis on the IL-10 locus, we identified one STAT-responsive element within intron 4, designated I-SRE-4, as an interspecies-conserved sequence. We found that I-SRE-4 acted as an enhancer element, and clustered CpGs around the I-SRE-4 were hypomethylated in IL-10-producing Treg cells, but not in other T cells. A gel-shift analysis using a nuclear extract from IL-2-stimulated HOZOT confirmed that CpG DNA methylation around I-SRE-4 reduced STAT5 binding to the element. Chromatin immunoprecipitation analysis revealed the in situ binding of IL-2-activated STAT5 to I-SRE-4. Thus, we provide molecular evidence for the involvement of an IL-2-STAT5 signaling axis in the expression of IL-10 by human Treg cells, an axis that is regulated by the intronic enhancer, I-SRE-4, and epigenetic modification of this element. |
| 巻・号 | 181(6) |
| ページ | 3897-905 |
| 公開日 | 2008-9-15 |
| DOI | 10.4049/jimmunol.181.6.3897 |
| PII | 181/6/3897 |
| PMID | 18768844 |
| MeSH | Animals Base Sequence Cell Line, Tumor Cells, Cultured Coculture Techniques Conserved Sequence Enhancer Elements, Genetic / immunology Epigenesis, Genetic / immunology Humans Interleukin-10 / biosynthesis* Interleukin-10 / genetics* Interleukin-10 / metabolism Interleukin-10 / physiology Interleukin-2 / physiology* Introns* Mice Molecular Sequence Data Protein Binding / genetics Protein Binding / immunology Response Elements / immunology* STAT5 Transcription Factor / metabolism* STAT5 Transcription Factor / physiology Signal Transduction / genetics Signal Transduction / immunology T-Lymphocytes, Regulatory / immunology* T-Lymphocytes, Regulatory / metabolism |
| IF | 4.886 |
| 引用数 | 61 |
| WOS 分野 | IMMUNOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | |