title: NFAT1 and JunB cooperatively regulate IL-31 gene expression in CD4+ T cells in health and disease.
abstract: IL-31 is a key mediator of itching in atopic dermatitis (AD) and is preferentially produced by activated CD4(+) T cells and Th2 cells. Although pathophysiological functions of IL-31 have been suggested in diverse immune disorders, the molecular events underlying IL-31 gene regulation are still unclear. In this study we identified the transcription start site and functional promoter involved in IL-31 gene regulation in mouse CD4(+) T cells. TCR stimulation-dependent IL-31 expression was found to be closely linked with in vivo binding of NFAT1 and JunB to the IL-31 promoter. Although NFAT1 alone enhanced IL-31 promoter activity, it was further enhanced in the presence of JunB. Conversely, knockdown of either NFAT1 or JunB resulted in reduced IL-31 expression. NFAT1-deficient CD4(+) T cells showed a significant defect in IL-31 expression compared with wild-type CD4(+) T cells. In agreement with these findings, mice subjected to atopic conditions showed much higher levels of IL-31, which were closely correlated with a significant increase in the number of infiltrated NFAT1(+)CD4(+) T cells into the AD ears. Amelioration of AD progression by cyclosporin A treatment was well correlated with downregulation of IL-31 expressions in CD4(+) T cells and total ear residual cells. In summary, our results suggest a functional cooperation between NFAT1 and JunB in mediating IL-31 gene expression in CD4(+) T cells and indicate that interference with this interaction or their activity has the potential of reducing IL-31-mediated AD symptoms.
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea;
authors.forename: Ji Sun
authors.initials: JS
authors.lastname: Hwang
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea;
authors.forename: Gi-Cheon
authors.initials: GC
authors.lastname: Kim
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea;
authors.forename: EunBee
authors.initials: E
authors.lastname: Park
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea;
authors.forename: Jung-Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea;
authors.forename: Chang-Suk
authors.initials: CS
authors.lastname: Chae
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea; School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea;
authors.forename: Won
authors.initials: W
authors.lastname: Hwang
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea; Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea; and.
authors.forename: Changhon
authors.initials: C
authors.lastname: Lee
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea; Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea; and.
authors.forename: Sung-Min
authors.initials: SM
authors.lastname: Hwang
authors.affiliation: Department of Neurosurgery, Chosun University College of Medicine, Gwangju 501-717, Republic of Korea.
authors.forename: Hui Sun
authors.initials: HS
authors.lastname: Wang
authors.affiliation: School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea;
authors.forename: Chang-Duk
authors.initials: CD
authors.lastname: Jun
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea;
authors.forename: Dipayan
authors.initials: D
authors.lastname: Rudra
authors.affiliation: Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea; Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea; and iimsh@postech.ac.kr.
authors.forename: Sin-Hyeog
authors.initials: SH
authors.lastname: Im
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D047369:Chromatin Immunoprecipitation; D003876:Dermatitis, Atopic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D007150:Immunohistochemistry; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D050778:NFATC Transcription Factors / Q000235:genetics / Q000276:immunology*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D059467:Transcriptome; D014162:Transfection
chemical_list: D007378:Interleukins; C584097:JunB protein, mouse; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; C502588:interleukin-31, mouse