Glucocorticoids Have Opposing Effects on Liver Fibrosis in Hepatic Stellate and Immune Cells

Mol Endocrinol. 2016 Aug;30(8):905-16. doi: 10.1210/me.2016-1029. Epub 2016 Jun 29.

Abstract

Liver fibrosis is a reversible wound-healing process that is protective in the short term, but prolonged fibrotic responses lead to excessive accumulation of extracellular matrix components that suppresses hepatocyte regeneration, resulting in permanent liver damage. Upon liver damage, nonparenchymal cells including immune cells and hepatic stellate cells (HSCs) have crucial roles in the progression and regression of liver fibrosis. Here, we report differential roles of the glucocorticoid receptor (GR), acting in immune cells and HSCs, in liver fibrosis. In the carbon tetrachloride hepatotoxin-induced fibrosis model, both steroidal and nonsteroidal GR ligands suppressed expression of fibrotic genes and decreased extracellular matrix deposition but also inhibited immune cell infiltration and exacerbated liver injury. These counteracting effects of GR ligands were dissociated in mice with conditional GR knockout in immune cells (GR(LysM)) or HSC (GR(hGFAP)): the impacts of dexamethasone on immune cell infiltration and liver injury were totally blunted in GR(LysM) mice, whereas the suppression of fibrotic gene expression was diminished in GR(hGFAP) mice. The effect of GR activation in HSC was further confirmed in the LX-2 HSC cell line, in which antifibrotic effects were mediated by GR ligand inhibition of Sma and mad-related protein 3 (SMAD3) expression. We conclude that GR has differential roles in immune cells and HSCs to modulate liver injury and liver fibrosis. Specific activation of HSC-GR without alteration of GR activity in immune cells provides a potential therapeutic approach to treatment of hepatic fibrosis.

MeSH terms

  • Animals
  • Carbon Tetrachloride / toxicity
  • Cell Line
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury / drug therapy
  • Chemical and Drug Induced Liver Injury / metabolism
  • Glucocorticoids / therapeutic use*
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Immunohistochemistry
  • Liver / cytology
  • Liver / drug effects
  • Liver / injuries
  • Liver / metabolism
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / metabolism*
  • Lymphocytes / drug effects
  • Lymphocytes / metabolism
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / metabolism
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / metabolism
  • Signal Transduction / drug effects

Substances

  • Glucocorticoids
  • RNA, Small Interfering
  • Receptors, Glucocorticoid
  • Carbon Tetrachloride

Grant support

This work was supported by the R. P. Doherty Jr.-Welch Chair in Science Grant Q-0022.