title: Transcriptional regulator CTR9 inhibits Th17 differentiation via repression of IL-17 expression.
abstract: PAF complex is an evolutionarily conserved transcriptional complex that associates with RNA polymerase II in the coding region of actively transcribing genes. Although its transcriptional activity is closely related to diverse cellular processes, such as cell-cycle progression or development in mammals, its role in immune responses has not been addressed yet. In this study, we show that CTR9, a component of PAF complex, functions as a repressor of Th17 differentiation. Both mRNA and protein levels of CTR9 were significantly decreased during the differentiation processes of naive T into Th17 effector cells. When CTR9 was depleted, IL-17 expression was induced and differentiation into Th17 cells enhanced. In naive T cells, CTR9 occupied the coding region of Il17a, but dissociated under Th17 in vitro-polarizing conditions. In contrast, both CDC73 and PAF1 were recruited to the Il17a locus under Th17-differentiation conditions. In the IL-6-stimulated splenocytes, expression of CTR9 was decreased, and chromatin-bound CTR9 disappeared in the coding region of Il17a. IL-6 also directly repressed expression of CTR9 gene, as promoter activity of CTR9 was similarly repressed by IL-6 treatment. Moreover, in mice with collagen-induced arthritis, lentivirus-mediated CTR9 overexpression in the joints ameliorated arthritis severity, decreasing the frequency of CD4(+)IL-17(+) T cells in lymph nodes. In conclusion, our data propose a novel feed-forward loop of IL-17 transcriptional regulatory circuit, via IL-6-mediated repression of CTR9 which is a transcriptional repressor of IL-17.
authors.affiliation: Division of Molecular and Life Sciences, Department of Life Sciences, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea;
authors.forename: Hyeon-Seok
authors.initials: HS
authors.lastname: Yoo
authors.forename: Yongwook
authors.initials: Y
authors.lastname: Choi
authors.forename: Narae
authors.initials: N
authors.lastname: Ahn
authors.forename: Saseong
authors.initials: S
authors.lastname: Lee
authors.forename: Wan-Uk
authors.initials: WU
authors.lastname: Kim
authors.forename: Min Seong
authors.initials: MS
authors.lastname: Jang
authors.forename: Myoung Ho
authors.initials: MH
authors.lastname: Jang
authors.forename: Yon Su
authors.initials: YS
authors.lastname: Kim
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Yoo
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000235:genetics*; D015850:Interleukin-6 / Q000378:metabolism*; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D058504:Th17 Cells / Q000166:cytology* / Q000276:immunology; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C529591:HRPT2 protein, mouse; C098680:Il17a protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D009687:Nuclear Proteins; C561966:PAF protein, mouse; D010750:Phosphoproteins; C547921:RNA polymerase II associated factor 1, mouse; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C099550:Sh2bp1 protein, mouse; C494087:Stat3 protein, mouse; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins