title: Distinct roles of transforming growth factor-beta-activated kinase 1 (TAK1)-c-Rel and interferon regulatory factor 4 (IRF4) pathways in human T cell lymphotropic virus 1-transformed T helper 17 cells producing interleukin-9.
abstract: Investigation of helper T cell markers in HTLV-1-transformed cell lines demonstrated that HuT-102 has an IL-9-producing Th17 phenotype. We confirmed the vital role of retinoic acid-related orphan receptor C, a Th17 transcription factor, in the expression of IL-17. Interferon regulatory factor 4 (IRF4), a transcription factor overexpressed in all HTLV-1-infected cells, regulated IL-17 and IL-9 concomitantly. We further demonstrated a novel pathway for the regulation of Tax-induced cytokines, IL-9 and IL-6, through TAK1-mediated nuclear accumulation of c-Rel. A microarray analysis for IRF4 knocked down HuT-102 cells showed a significant up-regulation in the set of genes related to Th1, mainly IFN-γ and several transcription factors. T-bet and IRF1, but not STAT1 and IRF9, participated in counteracting the inhibitory effect of IRF4 on the production of IFN-γ. Finally, suppression of both IRF4 and c-Rel resulted in the reduced proliferation. Collectively, these findings indicate that TAK1-c-Rel and IRF4 pathways play distinct roles in the maintenance of IL-9-producing Th17 phenotype of HTLV-1-transformed cells.
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan.
authors.forename: Alaa
authors.initials: A
authors.lastname: Refaat
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhou
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Suzuki
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takasaki
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.forename: Shoji
authors.initials: S
authors.lastname: Yamaoka
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Tabuchi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D015967:Gene Expression Regulation, Viral; D015368:Human T-lymphotropic virus 1 / Q000378:metabolism*; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D016906:Interleukin-9 / Q000096:biosynthesis* / Q000378:metabolism; D019169:Jurkat Cells; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D010641:Phenotype; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D034622:RNA Interference; D058504:Th17 Cells / Q000378:metabolism* / Q000821:virology*; D000099218:Interferon Regulatory Factor-4; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D050835:Interferon Regulatory Factors; D015850:Interleukin-6; D016906:Interleukin-9; D020930:MAP Kinase Kinase Kinases; D020569:Proto-Oncogene Proteins c-rel; D000099218:Interferon Regulatory Factor-4; D000099151:MAP Kinase Kinase Kinase 7