Nuclear presence of nuclear factor of activated T cells (NFAT) c3 and c4 is required for Toll-like receptor-activated innate inflammatory response of monocytes/macrophages.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 8904683 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3913 (Electronic) Linking ISSN: 08986568 NLM ISO Abbreviation: Cell Signal Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Elsevier Science Ltd
      Original Publication: Oxford ; New York : Pergamon Press, 1988-
    • Subject Terms:
      Immunity, Innate*; Cell Nucleus/*metabolism ; Macrophages/*metabolism ; NFATC Transcription Factors/*deficiency ; Signal Transduction/*immunology ; Toll-Like Receptors/*metabolism; Animals ; Bone Marrow/drug effects ; Bone Marrow/immunology ; Bone Marrow/metabolism ; Cell Nucleus/genetics ; Cell Nucleus/immunology ; Chromatin Immunoprecipitation ; Cytokines/genetics ; Cytokines/immunology ; Cytokines/metabolism ; Humans ; Immunohistochemistry ; Lipopeptides/pharmacology ; Lipopolysaccharides/pharmacology ; Macrophages/drug effects ; Macrophages/immunology ; Mice ; Mice, Knockout ; Monocytes/drug effects ; Monocytes/immunology ; Monocytes/metabolism ; NF-kappa B/genetics ; NF-kappa B/immunology ; NF-kappa B/metabolism ; NFATC Transcription Factors/genetics ; NFATC Transcription Factors/immunology ; NFATC Transcription Factors/metabolism ; Oligopeptides/pharmacology ; Primary Cell Culture ; RNA Polymerase II/antagonists & inhibitors ; RNA Polymerase II/genetics ; RNA Polymerase II/immunology ; RNA Polymerase II/metabolism ; RNA, Messenger/analysis ; Signal Transduction/drug effects ; Toll-Like Receptors/genetics ; Toll-Like Receptors/immunology ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/immunology ; Tumor Necrosis Factor-alpha/metabolism
    • Abstract:
      Nuclear factor of activated T cells (NFATs) are crucial transcription factors that tightly control proinflammatory cytokine expression for adaptive immunity in T and B lymphocytes. However, little is known about the role of NFATs for innate immunity in macrophages. In this study, we report that NFAT is required for Toll-like receptor (TLR)-initiated innate immune responses in bone marrow-derived macrophages (BMMs). All TLR ligand stimulation including LPS, a TLR4 ligand, and Pam(3)CSK(4), a TLR1/2 ligand, induced expression of TNF which was inhibited by VIVIT, an NFAT-specific inhibitor peptide. BMMs from NFATc4 knock-out mouse expressed less TNF than wild type. Despite apparent association between NFAT and TNF, LPS did not directly activate NFAT based on NFAT-luciferase reporter assay, whereas NF-κB was inducibly activated by LPS. Instead, macrophage exhibited constitutive NFAT activity which was not increased by LPS and was decreased by VIVIT. Immunocytochemical examination of NFATc1-4 of BMMs exhibited nuclear localization of NFATc3/c4 regardless of LPS stimulation. LPS stimulation did not cause nuclear translocation of NFATc1/c2. Treatment with VIVIT resulted in nuclear export of NFATc3/c4 and inhibited TLR-activated TNF expression, suggesting that nuclear residence of NFATc is required for TLR-related innate immune response. Chromatin immunoprecipitation (ChIP) assay using anti-RNA polymerase II (PolII) antibody suggested that VIVIT decreased PolII binding to TNF gene locus, consistent with VIVIT inhibition of LPS-induced TNF mRNA expression. This study identifies a novel paradigm of innate immune regulation rendered by NFAT which is a well known family of adaptive immune regulatory proteins.
      (Copyright © 2011 Elsevier Inc. All rights reserved.)
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    • Grant Information:
      R01 AR056246-02 United States AR NIAMS NIH HHS; R01 EB006834-03 United States EB NIBIB NIH HHS; R01AR056246 United States AR NIAMS NIH HHS; R01 EB006834-04 United States EB NIBIB NIH HHS; R01 AR056246 United States AR NIAMS NIH HHS; R01EB006834 United States EB NIBIB NIH HHS; R01 AR056246-04 United States AR NIAMS NIH HHS; R01 EB006834-02 United States EB NIBIB NIH HHS; R01 EB006834 United States EB NIBIB NIH HHS; R01 AR056246-01A1 United States AR NIAMS NIH HHS; R01 EB006834-01 United States EB NIBIB NIH HHS; R01 AR056246-03 United States AR NIAMS NIH HHS
    • Accession Number:
      0 (Cytokines)
      0 (Lipopeptides)
      0 (Lipopolysaccharides)
      0 (NF-kappa B)
      0 (NFATC Transcription Factors)
      0 (Oligopeptides)
      0 (Pam(3)CSK(4) peptide)
      0 (RNA, Messenger)
      0 (Toll-Like Receptors)
      0 (Tumor Necrosis Factor-alpha)
      0 (VIVIT peptide)
      0 (transcription factor NF-AT c3)
      EC 2.7.7.- (RNA Polymerase II)
    • Publication Date:
      Date Created: 20110706 Date Completed: 20111230 Latest Revision: 20220309
    • Publication Date:
      20240829
    • Accession Number:
      PMC3169434
    • Accession Number:
      10.1016/j.cellsig.2011.06.013
    • Accession Number:
      21726630