RRC ID 43455
Author 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.
Title 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.
Journal 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.
Volume 181(6)
Pages 3897-905
Published 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
Times Cited 61
Human and Animal Cells