Mesenchymal stem cells (MSCs) have been shown to have an immunomodulatory capability and clinical potential in immune diseases. However, it is unknown how MSCs may affect immunity in liver injury. This study was designed to explore the effect of bone marrow-derived MSCs (BM-MSCs) on hepatic natural killer (NK) cells in polyinosinic polycytidylic acid (PolyI:C)-induced liver injury. Unlike in controls, adoptive transfer of BM-MSCs in mice ameliorated Polyl:C-induced liver injury, as shown by lower alanine aminotransferase levels and decreased lymphocyte infiltration in the liver. Importantly, BM-MSCs suppress Nit cell accumulation and activation in the liver, which plays an important role in Polyl:C-induced liver injury. Furthermore, Nit cells co-cultured with BM-MSCs reduced expression of sphingosine-1-phosphate receptor type 5 (S1PR5), an important receptor required for NK cell trafficking in vivo. BM-MSC administration suppressed the elevation of expression of S1PR5 in the liver induced by PolyI:C injection. Accordingly, BM-MSCs inhibited the chemotactic activity of Nit cells induced by sphingosine-l-phosphate (SIP, the ligand of S1PR5). Our results provide an additional mechanism for the immunosuppressive effect of BM-MSCs on Nit cells, which further supports the therapeutic potential of BM-MSCs in immune-mediated disorders, including those in which Nit cells play a major role. (C) 2015 Elsevier Inc. All rights reserved.