Supported by Instituto Carlos III 00/0006/02 Dirección General de Drogodependencias, Generalitat Valenciana, Escuela Valenciana de Estudios para la Salud and Red de Transtornos Adictivos, Spain.
Chronic Ethanol Consumption Enhances Interleukin-1-Mediated Signal Transduction in Rat Liver and in Cultured Hepatocytes
Version of Record online: 3 MAY 2006
Alcoholism: Clinical and Experimental Research
Volume 27, Issue 12, pages 1979–1986, December 2003
How to Cite
Valles, S. L., Blanco, A. M., Azorin, I., Guasch, R., Pascual, M., Gomez-Lechon, M. J., Renau-Piqueras, J. and Guerri, C. (2003), Chronic Ethanol Consumption Enhances Interleukin-1-Mediated Signal Transduction in Rat Liver and in Cultured Hepatocytes. Alcoholism: Clinical and Experimental Research, 27: 1979–1986. doi: 10.1097/01.ALC.0000099261.87880.21
- Issue online: 3 MAY 2006
- Version of Record online: 3 MAY 2006
- Received for publication April 25, 2003; accepted September 4, 2003.
- Alcoholic Liver Disease;
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.