Increased concentrations and activity of plasma
cytokines produced by monocytes, macrophages, and hepatocytes in patients with
alcoholic liver diseases, correlate with the
clinical course of
liver diseases and are of prognostic value. Especially, high levels of circulating
tumor necrosis factor (
TNF)-alpha have been found to correlate with increased mortality in
alcoholic hepatitis. Moreover, hepatic
RANTES was increased in patients with
alcoholic hepatitis. Thus,
TNF-alpha-induced
RANTES expression may have a critical role in cell-mediated liver injury associated with
alcoholic hepatitis.
Fibrates are widely used in the treatment of
hyperlipidemia and lower
triglyceride levels in patients with
hyperlipidemia. Recently, several groups reported that
bezafibrate, one of
fibrates, is effective in
primary biliary cirrhosis treatment. Additionally, it is reported that
bezafibrate is effective in the treatment not only of
primary biliary cirrhosis but also of
chronic hepatitis C and
tamoxifen-induced non-
alcoholic steatohepatitis. We, here, presented that
bezafibrate and
fenofibrate repressed
TNF-alpha-induced
protein production and
mRNA expression of
RANTES in human hepatocyte-derived cells.
Luciferase assay showed that
bezafibrate and
fenofibrate inhibited
RANTES gene expression in response to
TNF-alpha. Moreover,
bezafibrate repressed
TNF-alpha-induced
DNA-binding activity of
NF-kappaB. Thus,
fibrates reduced
TNF-alpha-induced
NF-kappaB activation and
RANTES expression, possibly suggesting that
fibrates might be inhibitory agents of migration of inflammatory cells by
RANTES to the liver in patients with
alcoholic liver diseases. In line of these results, it might be possible that
fibrates are therapeutic agents in
alcoholic liver diseases.