Role of IL-17A in Neutrophil Recruitment and Hepatic Injury after Warm Ischemia-Reperfusion Mice

H. Kono, H. Fujii, M. Ogiku, N. Hosomura, H. Amemiya, M. Tsuchiya, M. Hara
2011 Journal of Immunology  
Recent evidence suggests that IL-17A regulates neutrophil-dependent organ injury. Accordingly, the purpose of this study was to determine the role of IL-17A in neutrophil recruitment after ischemia-reperfusion (I/R) and in subsequent liver injury. Two mouse models including wild-type and IL-17A knockout mice were evaluated for I/R injury. The medial largest lobe of the liver was clamped for 90 min. In another set of experiments, recombinant mouse (rm)IL-17A homodimer or rmIL-17A/F heterodimer
more » ... 17A/F heterodimer were administered to knockout mice before I/R, and liver injury was investigated. Isolated Kupffer cells were incubated with rmIL-17A or rmIL-17F, and production of TNF-a was measured. Studies evaluating the extent of liver injury as measured by serum transaminase levels demonstrated similar levels in the acute phase (6 h) in these two models. In contrast, in the subacute phase (20 h) after I/R, both serum transaminase levels and percent of hepatic necrosis were significantly reduced in the knockout mice compared with the wild-type mice. This reduction in liver injury seen in the knockout mice was associated with suppression of chemokine and adhesion molecule expression and reduction in infiltration of neutrophils into the liver. Administration of rmIL-17A homodimer, but not IL-17A/F heterodimer, increased liver injury in the subacute phase of I/R in KO mice. TNF-a production by isolated Kupffer cells increased significantly in the cells incubated with rmIL-17A compared with rmIL-17F. These results indicate that IL-17A is a key regulator in initiating neutrophil-induced inflammatory responses and hepatic injury in the subacute phase after reperfusion. Male wild-type mice (C57BL/6, 10-12 wk of age; obtained from The Jackson Laboratory, Bar Harbor, ME) and IL-17A knockout mice (backcrossed onto C57BL/6) were housed in a clean, temperature-controlled environment with a 12-h light-dark cycle and were given free access to Abbreviations used in this article: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ICAM-1, intercellular adhesion molecule 1; I/R, ischemia-reperfusion; LPM, liver perfusion medium; MPO, myeloperoxidase; rm, recombinant mouse; VEH, vehicle.
doi:10.4049/jimmunol.1100490 pmid:21949019 fatcat:fvxtxjhy25awtfwfxapfpcuc3a