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Tumor necrosis factor induces rapid down-regulation of TXNIP in human T cells

Trine B Levring1, Martin Kongsbak-Wismann1, Anna K O Rode1

  • 1The LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Scientific Reports
|November 15, 2019
PubMed

Insights

Tumor necrosis factor (TNF) rapidly down-regulates Thioredoxin interacting protein (TXNIP) in T cells, increasing glucose uptake. This TNF-induced TXNIP cleavage is caspase-dependent and may involve damage-associated molecular patterns during density gradient centrifugation.

Area of Science:

  • Immunology
  • Cellular Biology
  • Molecular Biology

Background:

  • T cell activation requires both antigen-specific and co-stimulatory signals.
  • Tumor necrosis factor receptor superfamily (TNFRSF) members provide co-stimulatory signals.
  • Thioredoxin interacting protein (TXNIP) inhibits glucose uptake and proliferation, but its regulation in T cells is unclear.

Purpose of the Study:

  • To investigate the expression and regulation of TXNIP in human T cells.
  • To understand the role of TNF and other stimuli in modulating TXNIP levels.
  • To elucidate the molecular mechanisms underlying TXNIP regulation in T cells.

Main Methods:

  • Analysis of TXNIP expression in naïve T cells.
  • Treatment of blood samples with TNF and toll-like receptor (TLR) ligands.
  • Assessment of glucose uptake following TNF treatment.
  • Investigation of TXNIP regulation during density gradient centrifugation (DGC).
  • Evaluation of caspase activity and TXNIP cleavage.

Main Results:

  • Naïve T cells exhibit high TXNIP expression.
  • TNF treatment rapidly down-regulates TXNIP in T cells, correlating with increased glucose uptake.
  • DGC induces TNF production and subsequent TXNIP down-regulation.
  • TLR ligand stimulation mimics DGC effects, suggesting a role for damage-associated molecular patterns (DAMPs).
  • TNF-induced TXNIP down-regulation is mediated by caspase activity and involves direct caspase-mediated cleavage of TXNIP.

Conclusions:

  • TXNIP is highly expressed in naïve T cells and its expression is tightly regulated.
  • TNF signaling, potentially triggered by DAMPs during procedures like DGC, leads to TXNIP cleavage and enhanced T cell glucose metabolism.
  • Caspase-mediated cleavage is the key mechanism for TNF-induced TXNIP down-regulation in T cells.

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