Interleukin-37 reduces liver inflammatory injury via effects on hepatocytes and non-parenchymal cells.
OBJECTIVE
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.
Department of Surgery, University of Cincinnati, Cincinnati, Ohio, USA.
Nozomu
N
Sakai
Heather L
HL
Van Sweringen
Ritha M
RM
Belizaire
Ralph Cutler
RC
Quillin
Rebecca
R
Schuster
John
J
Blanchard
Justin M
JM
Burns
Amit D
AD
Tevar
Michael J
MJ
Edwards
Alex B
AB
Lentsch
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000097:blood; D054426:Chemokine CXCL2 / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D007375:Interleukin-1 / Q000494:pharmacology*; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000098:blood supply / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation / Q000187:drug effects; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009195:Peroxidase / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D000893:Anti-Inflammatory Agents; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C508587:IL37 protein, human; D018836:Inflammation Mediators; D007375:Interleukin-1; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D013481:Superoxides; C052617:Bcl2 protein, mouse; D009195:Peroxidase; D000410:Alanine Transaminase