title: Natural killer cell functional dichotomy: a feature of chronic viral hepatitis?
abstract: Natural killer (NK) cells are involved in innate immune responses to viral infections either via direct cytotoxicity which destroys virus-infected cells or production of immunoregulatory cytokines which modulate adaptive immunity and directly inhibit virus replication. These functions are mediated by different NK subpopulations, with cytotoxicity being generally performed by CD56(dim) NK cells, whereas CD56(bright) NK cells are mainly involved in cytokine secretion. NK functional defects are usually combined so that impaired degranulation is often associated with deficient cytokine production. Innate immunity is thought to be relevant in the control of hepatitis virus infections such as hepatitis B virus (HBV) and hepatitis C virus (HCV), and recent findings reproducibly indicate that NK cells in chronic viral hepatitis are characterized by a functional dichotomy, featuring a conserved or enhanced cytotoxicity and a reduced production of interferon (IFN)-γ and tumor necrosis factor-α. In chronic HCV infection this appears to be caused by altered IFN-α signaling resulting from increased signal transducer and activator of transcription 1 (STAT1) phosphorylation, which polarizes NK cells toward cytotoxicity, and a concomitantly reduced IFN-α induced STAT4 phosphorylation yielding reduced IFN-γ mRNA levels. These previously unappreciated findings are compatible on the one hand with the inability to clear HCV and HBV from the liver and on the other they may contribute to understand why these patients are often resistant to IFN-α-based therapies.
authors: Research Laboratories, Department of Infectious Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo Pavia, Italy ; Department of Internal Medicine, University of Pavia Pavia, Italy.
authors: Mario U
authors: MU
authors: Mondelli
authors: Barbara
authors: B
authors: Oliviero
authors: Dalila
authors: D
authors: Mele
authors: Stefania
authors: S
authors: Mantovani
authors: Chiara
authors: C
authors: Gazzabin
authors: Stefania
authors: S
authors: Varchetta
keywords: HBV; HCV; IFN-α; IFN-γ; liver diseases