• Alcoholic Liver Disease;
  • NFκB;
  • IL-1β;
  • IRAK;
  • ERK1/2

Background: Interleukin-1 (IL-1) is a central mediator of the inflammatory process. Increased serum levels of IL-1 have been reported in alcoholics with liver damage, but it remains unknown whether chronic ethanol intake, in the presence or absence of lipopolysaccharide (LPS), activates IL-1 release and signaling in the hepatocyte.

Methods: IL-1β and IL-10 release, expression of their receptors (IL-1RI and IL-10R), and the IL-1RI signal transduction response were evaluated in livers and cultured hepatocytes from ethanol-fed or pair-fed rats exposed in vivo or in vitro to LPS, ethanol, or both.

Results: Chronic ethanol intake increased both the serum levels of IL-1β and IL-10 and the expression of IL-1RI, but not of IL-10R, in the liver microsomal fraction. In vivo LPS administration potentiated the ethanol-induced release of plasma cytokines. It is interesting to note that ethanol, either given in a single dose or chronically fed, stimulated IL-1β and IL-10 release from cultured hepatocytes. Stimulation of hepatocytes with IL-1β caused a higher activation of IL-1-associated kinase, extracellular receptor-activated kinases 1 and 2, and nuclear factor-κB (NF-κB) in hepatocytes from alcohol-fed animals than from controls. Furthermore, in the absence of any stimulation, hepatocytes from alcohol-fed animals showed an activation of both kinases, as well as an increase in NF-κB binding. Our results suggest the participation of the extracellular signal-regulated kinase (ERK)1/2 pathway in ethanol-induced NF-κB activation, because treatment with PD-98059, an ERK1/2 inhibitor, partially suppressed IL-1β-induced NF-κB expression.

Conclusions: Chronic ethanol intake potentiates the action of the proinflammatory cytokine IL-1β, enhancing the release and signaling response of IL-1β in the hepatocyte, which in conjunction with other cytokines or LPS may exacerbate the inflammatory damage associated with alcoholic liver disease.