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  • Title: T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner.
    Author: Uchida Y, Ke B, Freitas MC, Yagita H, Akiba H, Busuttil RW, Najafian N, Kupiec-Weglinski JW.
    Journal: Gastroenterology; 2010 Dec; 139(6):2195-206. PubMed ID: 20637206.
    Abstract:
    BACKGROUND & AIMS: T-cell immunoglobulin mucin (TIM) genes are expressed by T cells and regulate host immunity and tolerance. CD4(+) T cells mediate innate immunity-dominated liver ischemia-reperfusion injury (IRI) by unknown mechanisms. TIM-1 is involved in liver IRI, which is activated in part by the Toll-like receptor (TLR)4; we investigated the role of TIM-3 and TLR4 in IRI. METHODS: Using an antibody against TIM-3 (anti-TIM-3), we studied TIM-3 signaling in mice following partial warm liver ischemia and reperfusion. RESULTS: Mice given anti-TIM-3 had more liver damage than controls. Histological studies revealed that anti-TIM-3 increased hepatocellular damage and local neutrophil infiltration, facilitated local accumulation of T cells and macrophages, and promoted liver cell apoptosis. Intrahepatic neutrophil activity; induction of proinflammatory cytokines and chemokines; and expression of cleaved caspase-3, nuclear factor-κB, and TLR4 all increased in mice given anti-TIM-3. Administration of anti-TIM-3 followed by anti-galectin-9 (Gal-9 is a TIM-3 ligand) increased production of interferon-γ by concanavalin A (ConA)-stimulated spleen T cells and expression of tumor necrosis factor-α and interleukin-6 in ConA-stimulated macrophages co-cultured with T cells. Anti-TIM-3 did not affect liver IRI in TLR4-deficient mice. CONCLUSION: TIM-3 blockade exacerbated local inflammation and liver damage, indicating the importance of TIM-3-Gal-9 signaling in maintaining hepatic homeostasis. TIM-3-TLR4 cross-regulation determined the severity of liver IRI in TLR4-dependent manner; these findings provide important information about the modulation of innate vs adaptive responses in patients that received liver transplants. Negative co-stimulation signaling by hepatic T-cells might be developed to minimize innate immunity-mediated liver tissue damage.
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