Chronic ethanol consumption enhances interleukin-1-mediated signal transduction in rat liver and in cultured hepatocytes.
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-1beta 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-1beta 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-1beta and IL-10 release from cultured hepatocytes. Stimulation of hepatocytes with IL-1beta caused a higher activation of IL-1-associated kinase, extracellular receptor-activated kinases 1 and 2, and nuclear factor-kappaB (NF-kappaB) 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-kappaB binding. Our results suggest the participation of the extracellular signal-regulated kinase (ERK)1/2 pathway in ethanol-induced NF-kappaB activation, because treatment with PD-98059, an ERK1/2 inhibitor, partially suppressed IL-1beta-induced NF-kappaB expression.


CONCLUSIONS
Chronic ethanol intake potentiates the action of the proinflammatory cytokine IL-1beta, enhancing the release and signaling response of IL-1beta in the hepatocyte, which in conjunction with other cytokines or LPS may exacerbate the inflammatory damage associated with alcoholic liver disease.
Valles
Soraya L
SL
Instituto de Investigaciones Citológicas, Valencia, Spain.
Blanco
Ana M
AM
Azorin
Inmaculada
I
Guasch
Rosa
R
Pascual
María
M
Gomez-Lechon
María Jose
MJ
Renau-Piqueras
Jaime
J
Guerri
Consuelo
C
D000428:Alcohol Drinking / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D007375:Interleukin-1; D000431:Ethanol