Macrophage Migration Inhibitor Factor Upregulates MCP-1 Expression in an Autocrine Manner in Hepatocytes during Acute Mouse Liver Injury

Sci Rep. 2016 Jun 8;6:27665. doi: 10.1038/srep27665.


Macrophage migration inhibitor factor (MIF), a multipotent innate immune mediator, is an upstream component of the inflammatory cascade in diseases such as liver disease. Monocyte chemoattractant protein-1 (MCP-1), a highly representative chemokine, is critical in liver disease pathogenesis. We investigated the role of MIF in regulating hepatocytic MCP-1 expression. MIF and MCP-1 expression were characterized by immunochemistry, RT-PCR, ELISA, and immunoblotting in CCl4-treated mouse liver and isolated hepatocytes. MIF was primarily distributed in hepatocytes, and its expression increased upon acute liver injury. Its expression was also increased in injured hepatocytes, induced by LPS or CCl4, which mimic liver injury in vitro. MIF was expressed earlier than MCP-1, strongly inducing hepatocytic MCP-1 expression. Moreover, the increase in MCP-1 expression induced by MIF was inhibited by CD74- or CD44-specific siRNAs and SB203580, a p38 MAPK inhibitor. Further, CD74 or CD44 deficiency effectively inhibited MIF-induced p38 activation. MIF inhibitor ISO-1 reduced MCP-1 expression and p38 phosphorylation in CCl4-treated mouse liver. Our results showed that MIF regulates MCP-1 expression in hepatocytes of injured liver via CD74, CD44, and p38 MAPK in an autocrine manner, providing compelling information on the role of MIF in liver injury, and implying a new regulatory mechanism for liver inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autocrine Communication*
  • Biomarkers
  • Carbon Tetrachloride / adverse effects
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemokine CCL2 / genetics*
  • Chemokine CCL2 / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation*
  • Hepatocytes / metabolism*
  • Liver Diseases / genetics*
  • Liver Diseases / metabolism*
  • Liver Diseases / pathology
  • Macrophage Migration-Inhibitory Factors / metabolism*
  • Mice
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Biomarkers
  • Chemokine CCL2
  • Macrophage Migration-Inhibitory Factors
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • Carbon Tetrachloride
  • p38 Mitogen-Activated Protein Kinases