TXNIP Regulates Natural Killer Cell-Mediated Innate Immunity by Inhibiting IFN-γ Production during Bacterial Infection

Int J Mol Sci. 2020 Dec 14;21(24):9499. doi: 10.3390/ijms21249499.


The function of natural killer (NK) cell-derived interferon-γ (IFN-γ) expands to remove pathogens by increasing the ability of innate immune cells. Here, we identified the critical role of thioredoxin-interacting protein (TXNIP) in the production of IFN-γ in NK cells during bacterial infection. TXNIP inhibited the production of IFN-γ and the activation of transforming growth factor β-activated kinase 1 (TAK1) activity in primary mouse and human NK cells. TXNIP directly interacted with TAK1 and inhibited TAK1 activity by interfering with the complex formation between TAK1 and TAK1 binding protein 1 (TAB1). Txnip-/- (KO) NK cells enhanced the activation of macrophages by inducing IFN-γ production during Pam3CSK4 stimulation or Staphylococcus aureus (S. aureus) infection and contributed to expedite the bacterial clearance. Our findings suggest that NK cell-derived IFN-γ is critical for host defense and that TXNIP plays an important role as an inhibitor of NK cell-mediated macrophage activation by inhibiting the production of IFN-γ during bacterial infection.

Keywords: IFN-γ; NK cell; TAK1; TXNIP; bacterial infection; toll-like receptor (TLR).

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Immunity, Innate / drug effects
  • Immunity, Innate / genetics
  • Interferon-gamma / metabolism*
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / metabolism*
  • Lipopeptides / pharmacology
  • Mice
  • Mice, Knockout
  • Staphylococcal Infections / genetics
  • Staphylococcal Infections / immunology
  • Staphylococcal Infections / metabolism
  • Staphylococcus aureus / pathogenicity
  • Thioredoxins / genetics
  • Thioredoxins / metabolism*
  • Toll-Like Receptors / genetics
  • Toll-Like Receptors / metabolism
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism


  • Carrier Proteins
  • Lipopeptides
  • Pam(3)CSK(4) peptide
  • Toll-Like Receptors
  • Transcription Factor AP-1
  • Txnip protein, mouse
  • Thioredoxins
  • Interferon-gamma