*Purpose: Portal vein hypertension (PHT) is associated with poor prognosis, risk factors for small graft syndrome, bloodstream infection, and acute rejection after living donor liver transplantation. We have recently reported that liver-resident natural killer cells (lr-NK cells) activity reduced via IL-33 signal in PHT mice model, depending on tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).To clarify the weakening mechanism of lr-NK cells’ function, we focused on IL-33, a cytokine released as DAMPs, due to sinusoidal endothelial cell injury and hepatocyte injury caused by portal hypertension and blood flow disturbance, using a PHT mice model.

*Methods: The right branch of the portal vein was selectively ligated as PHT mice model, and the left hepatic lobe on the non-ligated side was evaluated. The lr-NK cell activity was evaluated by flowcytometory, cytotoxicity test and expression analysis of IL-33 signaling in lr-NK cells by quantitative PCR method.

*Results: (1) TRAIL expression of lr-NK cells improved in anti-IL-33 treated PHT model. (p<0.05, 5 mice per group). (2) The Ingenuity-based URA predicted that various pathways were differentially activated between TRAIL+ vs. TRAIL- NK cell subsets. Foxo1 and MAPK1 were detected as TRAIL-inhibited genes, which were reported to be induced by IL-33. (3) Akt-Foxo and MAPK signaling in lr NK cells were analyzed by qRT-PCR 1h after co-cultured with IL-33. mRNA expression of PI3K, MAPK1, Tbx-21 and EOMES in lr- NK cells increased 1h after co-cultured with IL-33. On the other hand, mRNA expression of Foxo1 and TNFSF10 in lr-NK cells decreased 1h after co-cultured with IL-33.

*Conclusions: Akt-Foxo and MAPK signaling through IL-33/ST2 in lr- NK cells play a negative role on TRAIL expression of lr- NK cells in PHT mice.

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