Interleukin-37 reduces liver inflammatory injury via effects on hepatocytes and non-parenchymal cells

J Gastroenterol Hepatol. 2012 Oct;27(10):1609-16. doi: 10.1111/j.1440-1746.2012.07187.x.


Background and aim: The purpose of the present study was to determine the effects of interleukin-37 (IL-37) on liver cells and on liver inflammation induced by hepatic ischemia/reperfusion (I/R).

Methods: Mice were subjected to I/R. Some mice received recombinant IL-37 (IL-37) at the time of reperfusion. Serum levels of alanine aminotransferase, and liver myeloperoxidase content were assessed. Serum and liver tumor necrosis factor-α (TNF-α), macrophage inflammatory protein-2 (MIP-2) and keratinocyte chemokine (KC) were also assessed. Hepatic reactive oxygen species (ROS) levels were assessed. For in vitro experiments, isolated hepatocytes and Kupffer cells were treated with IL-37 and inflammatory stimulants. Cytokine and chemokine production by these cells were assessed. Primary hepatocytes underwent induced cell injury and were treated with IL-37 concurrently. Hepatocyte cytotoxicity and Bcl-2 expression were determined. Isolated neutrophils were treated with TNF-α and IL-37 and neutrophil activation and respiratory burst were assessed.

Results: IL-37 reduced hepatocyte injury and neutrophil accumulation in the liver after I/R. These effects were accompanied by reduced serum levels of TNF-α and MIP-2 and hepatic ROS levels. IL-37 significantly reduced MIP-2 and KC productions from lipopolysaccharide-stimulated hepatocytes and Kupffer cells. IL-37 significantly reduced cell death and increased Bcl-2 expression in hepatocytes. IL-37 significantly suppressed TNF-α-induced neutrophil activation.

Conclusions: IL-37 is protective against hepatic I/R injury. These effects are related to the ability of IL-37 to reduce proinflammatory cytokine and chemokine production by hepatocytes and Kupffer cells as well as having a direct protective effect on hepatocytes. In addition, IL-37 contributes to reduce liver injury through suppression of neutrophil activity.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Anti-Inflammatory Agents / pharmacology*
  • Cells, Cultured
  • Chemokine CXCL1 / blood
  • Chemokine CXCL2 / blood
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Hepatitis / immunology
  • Hepatitis / metabolism
  • Hepatitis / pathology
  • Hepatitis / prevention & control*
  • Hepatocytes / drug effects*
  • Hepatocytes / immunology
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Inflammation Mediators / blood
  • Interleukin-1 / pharmacology*
  • Kupffer Cells / drug effects
  • Kupffer Cells / immunology
  • Liver / blood supply
  • Liver / drug effects*
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neutrophil Activation / drug effects
  • Neutrophil Infiltration / drug effects
  • Neutrophils / drug effects
  • Neutrophils / immunology
  • Peroxidase / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins / pharmacology
  • Reperfusion Injury / immunology
  • Reperfusion Injury / metabolism
  • Reperfusion Injury / pathology
  • Reperfusion Injury / prevention & control*
  • Superoxides / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / blood


  • Anti-Inflammatory Agents
  • Chemokine CXCL1
  • Chemokine CXCL2
  • Cxcl1 protein, mouse
  • Cxcl2 protein, mouse
  • IL37 protein, human
  • Inflammation Mediators
  • Interleukin-1
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Superoxides
  • Bcl2 protein, mouse
  • Peroxidase
  • Alanine Transaminase