Hepatoprotective and anti-inflammatory cytokines in alcoholic liver disease

Abstract

The activation of innate immunity by various factors (e.g. lipopolysaccharide and complements) plays an important role in initiating and promoting alcoholic liver injury via the stimulation of Kupffer cells to induce oxidative stress and to produce pro-inflammatory cytokines (e.g. tumor necrosis factor [TNF]-α) that cause hepatocellular damage. Accumulating evidence suggests that the activation of innate immunity also stimulates Kupffer cells to produce the hepatoprotective cytokine interleukin-6 (IL-6) and the anti-inflammatory cytokine IL-10 during alcoholic liver injury. IL-6 protects against alcoholic liver injury via the activation of signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via the activation of STAT3 in Kupffer cells/macrophages and the subsequent inhibition of liver inflammation. Recent studies have suggested that IL-10 may play a dual role in controlling ethanol-induced steatosis and liver injury via the inhibition of the pro-inflammatory cytokine TNF-α, thereby ameliorating alcoholic liver injury, or via the inhibition of the hepatoprotective cytokine IL-6, thereby potentiating alcoholic liver injury. IL-22 is another important hepatoprotective cytokine that protects against acute and chronic alcoholic liver injury by binding to a receptor complex composed of IL-10R2 and IL-22R chains on the surfaces of hepatocytes. Finally, IL-22 treatment is a potential therapeutic option for treating severe forms of alcoholic liver disease because of its antioxidant, antiapoptotic, antisteatotic, proliferative, and antimicrobial effects, as well as the potential added benefit of few side effects.

Fig. 1. IL-6-, IL-22-, and IL-10-induced activation of STAT3 in the liver

In hepatocytes, both IL-6 and IL-22 induce STAT3 activation and play important roles in hepatoprotection and liver regeneration. In Kupffer cells, IL-6 induces transient STAT3 activation and contributes to the pro-inflammatory response, whereas IL-10 induces prolonged STAT3 activation and contributes to the anti-inflammatory response. In sinusoidal endothelial cells, IL-6 induces STAT3 activation and subsequently promotes cell survival. In hepatic stellate cells, IL-6 induces STAT3 activation; however, the roles of STAT3 in stellate cell activation and fibrogenesis remain obscure.

Fig. 2. Elevations of IL-6 and IL-10 are part of a host defense strategy to repair the injured liver and control inflammation in ALD

Chronic alcohol consumption leads to innate immunity activation via various factors (e.g., LPS, TNF-α, and complement), with subsequent hepatocellular damage. The activation of innate immunity also promotes the production of the hepatoprotective cytokine IL-6, which plays an important compensatory role in repairing liver damage via the activation of STAT3 and the upregulation of multiple hepatoprotective genes in hepatocytes. The activation of innate immunity also produces the anti-inflammatory cytokine IL-10, which activates STAT3 in Kupffer cells/macrophages and controls liver inflammation. However, IL-10 plays a dual role in controlling alcoholic fatty liver and liver injury: first, IL-10 inhibits LPS, TNF-α, and complement activation, thereby reducing steatosis and liver damage; second, IL-10 blocks IL-6 production, thereby reducing liver regeneration and enhancing steatosis and liver damage.