Activation of natural killer cells inhibits liver fibrosis: a novel strategy to treat liver fibrosis.

Liver lymphocytes are enriched in natural killer (NK) cells, which are involved in innate immune defenses against viral infection and tumor transformation in the liver. Recent evidence indicates that NK cell activation by IFN-alpha, IFN-gamma or dsRNA attenuates liver fibrosis through the direct killing of activated hepatic stellate cells (HSCs). Interestingly, NK cells do not kill quiescent or fully activated HSCs, but only early-activated HSCs, as only these cells express elevated levels of the NK cell-activating ligand retinoic acid-induced early transcript (RAE)-1 and TNF-related apoptosis-inducing ligand receptors, in addition to downregulated levels of the NK-cell inhibitory ligand, MHC-I. Inhibition of liver fibrosis by NK cells can also be achieved through production of IFN-gamma, which induces HSC cell cycle arrest and apoptosis in a STAT1-dependent manner. Clinically, it has also been observed that NK cell activity is negatively correlated with liver fibrosis in patients with chronic hepatitis C infection. Therefore, since NK cells inhibit liver fibrosis, stimulating NK activity could potentially be a novel strategy to treat liver fibrosis. Clinical studies will be required to confirm whether stimulating NK cell activity is effective and safe in treating human liver fibrosis.