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A distal cis-regulatory element, CNS-9, controls NFAT1 and IRF4-mediated IL-10 gene activation in T helper cells

Authors
 Choong-Gu Lee  ;  Kyu-Ho Kang  ;  Jae-Seon So  ;  Ho-Keun Kwon  ;  Jun-Seock Son  ;  Min-Kyung Song  ;  Anupama Sahoo  ;  Hwa-Joong Yi  ;  Ki-Chul Hwang  ;  Toshifumi Matsuyama  ;  Katsuyuki Yui  ;  Sin-Hyeog Im 
Citation
 MOLECULAR IMMUNOLOGY, Vol.46(4) : 613-621, 2009 
Journal Title
 MOLECULAR IMMUNOLOGY 
ISSN
 0161-5890 
Issue Date
2009
MeSH
Animals ; Cell Line, Tumor ; Cyclosporine/pharmacology ; Enhancer Elements, Genetic/genetics* ; Humans ; Interferon Regulatory Factors/genetics* ; Interferon Regulatory Factors/metabolism ; Interleukin-10/genetics* ; Interleukin-10/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; NFATC Transcription Factors/genetics* ; NFATC Transcription Factors/metabolism ; Signal Transduction/genetics ; Th1 Cells/metabolism ; Th2 Cells/drug effects ; Th2 Cells/immunology* ; Th2 Cells/metabolism ; Transcriptional Activation*
Keywords
Th1/Th2 Cells ; Cytokines ; Transcription factors ; Gene regulation ; Molecular immunology
Abstract
IL-10 is a multifunctional cytokine that plays a critical role in maintaining the balance between immunity and tolerance. Previously, we identified proximal regulatory elements and alterations of chromatin structure in the IL-10 gene loci of Th1 and Th2 cells. We have now characterized a crucial cis-regulatory element, CNS-9, located 9kb upstream of the transcription start site in IL-10 gene loci. The CNS-9 region is highly conserved in vertebrate genomes, and contains clustered NFAT and IRF binding motifs. In vitro binding of NFAT1 and IRF4 to the CNS-9 region was observed by EMSA. Furthermore, Th2-preferential in vivo binding of NFAT1 and IRF4 to the CNS-9 region was observed by ChIP. Cyclosporine A treatment on wild type Th2 cells or Th2 cells derived from NFAT1 knockout (NFAT1(-/-)) mice showed significantly reduced trans-activity of CNS-9. The Th2 subset-specific enhancer activity of CNS-9 was upregulated synergistically by NFAT1 and its partner IRF4. Mutations in the binding sites for NFAT1 and IRF4 abrogated its enhancer activity of CNS-9. Collectively, our results establish crucial roles for enhancer element CNS-9, and NFAT1 and IRF4 that bind to it, for IL-10 expression in differential T helper subsets.
Full Text
http://www.sciencedirect.com/science/article/pii/S0161589008003313
DOI
10.1016/j.molimm.2008.07.037
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Hwang, Ki Chul(황기철)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/104978
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