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Diclofenac inhibits tumor necrosis factor-α-induced nuclear factor-κB activation causing synergistic hepatocyte

Lisa Fredriksson1, Bram Herpers, Giulia Benedetti

  • 1Division of Toxicology, Leiden/Amsterdam Centre for Drug Research, Leiden University, The Netherlands.

Hepatology (Baltimore, Md.)
|March 25, 2011
PubMed
Abstract

Insights

Diclofenac sensitizes liver cells to apoptosis by disrupting survival signals. This drug-induced liver injury mechanism involves suppressing tumor necrosis factor-alpha (TNF-α) pathways, increasing cell death.

Area of Science:

  • Hepatology
  • Immunology
  • Cellular Biology

Background:

  • Drug-induced liver injury (DILI) is a significant clinical issue.
  • The precise mechanisms of DILI at the hepatocyte level, particularly the interplay between drug toxicity and immune responses, remain unclear.
  • Understanding these mechanisms is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the cellular mechanisms underlying hepatocyte apoptosis induced by diclofenac and tumor necrosis factor-alpha (TNF-α).
  • To elucidate the crosstalk between drug toxicity and inflammatory signaling in liver cells.
  • To identify key molecular pathways involved in diclofenac-induced liver injury.

Main Methods:

  • Utilized HepG2 cells treated with diclofenac and TNF-α.
  • Employed a focused apoptosis machinery short interference RNA (siRNA) library screen.
  • Performed live cell imaging of GFPp65/RelA to monitor nuclear factor kappaB (NF-κB) translocation.
  • Assessed apoptosis, necrosis, and signaling pathway activation (JNK, NF-κB, IκBα).
  • Used specific inhibitors (BMS-345541) and short hairpin RNA (shRNA) for gene knockdown.

Main Results:

  • Diclofenac alone induced mild hepatocyte apoptosis, which was significantly enhanced by TNF-α.
  • The TNF-α-mediated potentiation involved caspase-3 activation via a caspase-8/Bid/APAF1 pathway.
  • Diclofenac suppressed TNF-α-induced NF-κB translocation and transcriptional activity by inhibiting IκBα phosphorylation.
  • Sustained c-Jun N-terminal kinase (JNK) activation by diclofenac contributed to apoptosis.
  • Inhibition of IKKβ or p65/RelA sensitized hepatocytes to diclofenac/TNF-α-induced cell death.

Conclusions:

  • Diclofenac-induced stress signaling suppresses TNF-α-mediated survival pathways in hepatocytes.
  • This suppression sensitizes liver cells to apoptosis, contributing to DILI.
  • The findings provide a mechanistic model for diclofenac-induced liver injury involving immune crosstalk at the cellular level.

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