The emerging role of T cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse.
The T cell immunoglobulin and mucin domain-containing molecules (TIM) protein family, which is expressed by T cells, plays a crucial role in regulating host adaptive immunity and tolerance. However, its role in local inflammation, such as innate immunity-dominated organ ischemia-reperfusion injury (IRI), remains unknown. Liver IRI occurs frequently after major hepatic resection or liver transplantation. Using an antagonistic anti-TIM-1 antibody (Ab), we studied the role of TIM-1 signaling in the model of partial warm liver ischemia followed by reperfusion. Anti-TIM-1 Ab monotherapy ameliorated the hepatocellular damage and improved liver function due to IR, as compared with controls. Histological examination has revealed that anti-TIM-1 Ab treatment decreased local neutrophil infiltration, inhibited sequestration of T lymphocytes, macrophages, TIM-1 ligand-expressing TIM-4(+) cells, and reduced liver cell apoptosis. Intrahepatic neutrophil activity and induction of proinflammatory cytokines/chemokines were also reduced in the treatment group. In parallel in vitro studies, anti-TIM-1 Ab suppressed interferon-gamma (IFN-gamma) production in concanavalin A (conA)-stimulated spleen T cells, and diminished tumor necrosis factor alpha (TNF-alpha)/interleukin (IL)-6 expression in a macrophage/spleen T cell coculture system. This is the first study to provide evidence for the novel role of TIM-1 signaling in the mechanism of liver IRI. TIM-1 regulates not only T for the role of cell activation but may also affect macrophage function in the local inflammation response. These results provide compelling data for further investigation of TIM-1 pathway in the mechanism of IRI, to improve liver function, expand the organ donor pool, and improve the overall success of liver transplantation.
Uchida
Yoichiro
Y
Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Ke
Bibo
B
Freitas
Maria Cecilia S
MC
Ji
Haofeng
H
Zhao
Danyun
D
Benjamin
Elizabeth R
ER
Najafian
Nader
N
Yagita
Hideo
H
Akiba
Hisaya
H
Busuttil
Ronald W
RW
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D017209:Apoptosis; D002450:Cell Communication; D016207:Cytokines / Q000096:biosynthesis; D000072596:Hepatitis A Virus Cellular Receptor 1; D007511:Ischemia / Q000209:etiology*; D008099:Liver / Q000098:blood supply* / Q000473:pathology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D015427:Reperfusion Injury / Q000209:etiology*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins