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

Nozomu Sakai, Heather L Van Sweringen, Ritha M Belizaire, Ralph Cutler Quillin, Rebecca Schuster, John Blanchard, Justin M Burns, Amit D Tevar, Michael J Edwards, Alex B Lentsch
Journal of Gastroenterology and Hepatology 2012, 27 (10): 1609-16

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.

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