Immunosuppressive effects of bile and bile acids on natural killer cell activity

Objective: Patients with severe liver diseases have been demonstrated to display low natural killer (NK) cell activity. In this context, it is important to note that bile acids have been shown to be involved in cellular immunological processes and to suppress cell-mediated innate and adaptive immunity. Here, we investigated the effects of human bile and bile acids on phenotype and function of human conventional NK cells (cNK). Methods: Freshly isolated cNK cells form healthy donors [n = 10] were incubated in bile (diluted 1:1000/500/250/100) or the bile acids ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA) (50/100/200µM/mL) for 15 hours. Then, cNK cell phenotype as well degranulation (CD107a) and IFN-γ was studied following incubation with either K562 or the human duodenal adenocarcinoma cell line HuTu80 using flow cytometry. Results: We found incubation of healthy cNK cells in human bile or CDCA to result in a significantly decreased expression of the activating NK cell receptors NKp46 and NKG2D. Moreover, cNK cell activation, assessed by measuring CD69 expression, was significantly reduced in bile and bile acid treated cNK cells. More importantly, we found both cytotoxic activity against HuTu80 cells as well as cNK cell IFN-γ production to be significantly decreased following incubation in the presence of bile/bile acids. Conclusion: Our data suggest the human bile and bile acids can impair cNK cell functions which might contribute to the immunpathogenesis of liver disease.