Synergy between TLR3 and IL-18 promotes IFN-gamma dependent TRAIL expression in human liver NK cells

Natural killer (NK) cells are a component of innate immunity against viral infections through their rapid cytotoxic activity and cytokine production. However, intra-hepatic NK cells' ability to respond to virus is still mostly unknown. Our results show that the synthetic dsRNA polyinosinic-polycytidylic acid (poly I:C), a mimic of a common product of viral infections, activates NK cells directly in the context of cytokines found in the liver, i.e.: poly I:C plus inflammatory cytokines (IL-18, IL-12, and IL-2) induced NK cell IFN-gamma production and TRAIL expression, and anti-inflammatory cytokines (TGF-beta and IL-10) inhibit NK cell IFN-gamma production. Neutralization of IFN-gamma blocks poly I:C plus inflammatory cytokines-induced NK cell TRAIL expression, suggesting that IFN-gamma is an autocrine differentiation factor for these cells. A better understanding of the intra-hepatic NK cell activation against viral infection may help in the design of therapies and vaccines for the control of viral hepatitis. (C) 2011 Elsevier Inc. All rights reserved.