Cytokines in acute liver inflammation and in chronic evolution of viral hepatitis

Cytokines constitute a complex network of molecules involved in the regulation of the inflammatory response and the homeostasis of organ functions. Cytokines coordinate physiologic and pathologic processes going on in the liver, such as liver growth and regeneration, inflammatory processes including viral liver disease, liver fibrosis and cirrhosis. Liver growth and regeneration are regulated by several cytokines. The platelet-derived hepatocyte growth factor, in particular, delivers a strong mitogenic stimulus for hepatocyte regeneration. The cell-mediated immune response plays a central role in hepatocellular necrosis and in the immunopathogenetic mechanisms involved in viral clearance and persistence in liver disease of viral etiology. In this context, cytokines modulate the immune system and exert direct antiviral activity by cytopathic and non-cytopathic mechanisms,as demonstrated in a transgenic mouse model. IL-6, TNF-α, IL-1 and IL-2 increase in acute fulminant viral hepatitis; in fact, they have pro-inflammatory and cytotoxic effects. Reduced IL-2 and IFN-α synthesis and increased serum levels of IL-1 and IL-2 soluble receptor (IL-2R) have been observed in HBV chronic liver disease. In HCV chronic hepatitis, IL-2R increases as well, while IFN-γ and IL-2 decrease. In personal experimental observations, intrahepatic messenger RNA expression of several cytokines was measured in liver specimens of patients with chronic HBV and HCV infections: patients with HCV chronic liver disease had higher levels of IL-2, IL-6, IL-10, and IFN-γ. These data are in accordance with immunological studies showing a vigorous cell-mediated immune response in HCV chronic liver disease and a deficient immune response in HBV chronic hepatitis. The main cytokines involved in the mechanisms of liver fibrosis and cirrhosis are also discussed.