2. Academic Validation
  3. 6-Methoxyflavone inhibits NFAT translocation into the nucleus and suppresses T cell activation

6-Methoxyflavone inhibits NFAT translocation into the nucleus and suppresses T cell activation

  • J Immunol. 2014 Sep 15;193(6):2772-83. doi: 10.4049/jimmunol.1400285.
Jae-Seon So 1,  Gi-Cheon Kim 2,  Minkyung Song 3,  Choong-Gu Lee 4,  Eunbee Park 2,  Ho Jin Kim 5,  Young Sup Kim 6,  Chang-Duk Jun 7,  Sin-Hyeog Im 8
Affiliations

Affiliations

  • 1 School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021;
  • 2 School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea; Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea;
  • 3 School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea; Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY 10021;
  • 4 Academy of Immunology and Microbiology, Institute for Basic Science, Pohang 790-784, Republic of Korea;
  • 5 National Cancer Center, Korea, Goyang 410-769, Republic of Korea;
  • 6 Division of Drug Discovery Research, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; and.
  • 7 School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea;
  • 8 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 iimsh@postech.ac.kr.
PMID: 25114106 DOI: 10.4049/jimmunol.1400285
Abstract

NFAT plays a crucial role in the immune system by regulating the transcription of inducible genes during immune responses. In T cells, NFAT proteins govern various cellular events related to T cell development, activation, tolerance induction, and differentiation. We previously reported the NFAT1-dependent enhancer activity of conserved noncoding sequence (CNS)-9, a distal cis-acting element, in the regulation of IL-10 transcription in T cells. In this study, we developed a T cell-based reporter system to identify compounds that modulate the regulatory activity of CNS-9. Among the identified candidates, 6-methoxyflavone (6-MF) significantly inhibited the enhancer activity of CNS-9, thereby reducing IL-10 expression in T cells without affecting cell viability. 6-MF also downregulated the transcription of NFAT1 target genes such as IL-4, IL-13, and IFN-γ. Treatment of 6-MF inhibited the translocation of NFAT1 into the nucleus, which consequently interrupted NFAT1 binding to the target loci, without affecting the expression or dephosphorylation of NFAT1. Treatment of 6-MF to CD4(+) T cells or B cells isolated from mice with atopic dermatitis significantly reduced disease-associated cytokine production, as well as the levels of IgE. In addition, oral administration of 6-MF to atopic dermatitis mice ameliorated disease symptoms by reducing serum IgE levels and infiltrating lymphocytes. Conclusively, our results suggest that 6-MF can be a potential candidate for the development of an effective immunomodulator via the suppression of NFAT-mediated T cell activation.

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