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Cell-Specific Regulation of Inflammatory Cytokines and Acute-Phase Proteins by the Glucocorticoid Receptor

Rebecca Winkler1, Hong Lu1

  • 1Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA.

Mediators of Inflammation
|December 2, 2024
PubMed
Abstract

Insights

Glucocorticoid receptor (GR) differentially regulates chemokine expression in liver cells, inhibiting CXCL1 and CXCL8 while having cell-specific effects on CXCL2. This suggests potential therapeutic strategies for inflammatory liver diseases by modulating GR activity.

Area of Science:

  • Molecular biology
  • Immunology
  • Hepatology

Background:

  • Inflammatory liver diseases are associated with altered chemokine expression, including increased CXCL1 and CXCL8 and decreased CXCL2.
  • The role of the glucocorticoid receptor (GR) in modulating chemokine and acute-phase protein expression in the liver during infection or inflammation is not fully understood.

Purpose of the Study:

  • To investigate the effects of the glucocorticoid receptor (GR) on chemokine expression in human liver cells.
  • To understand how GR influences CXCL1, CXCL2, and CXCL8 expression in response to inflammatory stimuli like lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNFα).

Main Methods:

  • Primary human hepatocytes (PHH) were treated with TNFα, LPS, and dexamethasone (DEX).
  • Chemokine mRNA and protein levels were quantified using qPCR and ELISA.
  • Dual luciferase assays with wild-type and mutant CXCL2 promoters in various cell lines (HEK293T, HEPG2) were used to identify GR-responsive regions.

Main Results:

  • GR exhibited cell-specific effects: it inhibited CXCL1 and CXCL8 in PHH and HEK293T cells but showed varied effects on CXCL2.
  • In hepatocytes (PHH, HEPG2), GR activity influenced CXCL2 promoter activity differently compared to non-hepatic cells (HEK293T).
  • A specific 407-bp region of the CXCL2 promoter was crucial for GR activity in HEPG2 cells, with TNFα synergizing with HNF4α.

Conclusions:

  • GR's impact on chemokine expression is both cell-type and chemokine-specific.
  • The differential regulation of CXCL2 by GR in hepatocytes versus non-hepatocytes is mediated by cell-specific promoter utilization.
  • Targeting GR in the liver may offer a strategy to correct chemokine imbalances and mitigate sepsis in inflammatory liver conditions.

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