Inhibition of TNF-α-induced RANTES expression in human hepatocyte-derived cells by fibrates, the hypolipidemic drugs

Abstract

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)-α have been found to correlate with increased mortality in alcoholic hepatitis. Moreover, hepatic RANTES was increased in patients with alcoholic hepatitis. Thus, TNF-α-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-α-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-α. Moreover, bezafibrate repressed TNF-α-induced DNA-binding activity of NF-κB. Thus, fibrates reduced TNF-α-induced NF-κB 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.

Introduction

Alcoholic liver diseases are the dominant precursor lesion in those subjects consuming excessive quantities of alcohol who eventually develop from fatty liver to cirrhosis [1], [2], [3], [4]. Increased concentrations and activity of plasma cytokines produced by monocytes, macrophages, and hepatocytes in patients with alcoholic liver disease, correlate with the clinical course of liver disease and are of prognostic value [5], [6], [7], [8]. Especially, high levels of circulating tumor necrosis factor (TNF)-α have been found to correlate with increased mortality in alcoholic hepatitis [6], [9], [10], [11]. Moreover, Maltby et al. [12] reported that hepatic RANTES was increased in patients with alcoholic hepatitis. In experimental alcoholic liver disease in rats, RANTES was elevated in hepatocytes [13]. RANTES mainly migrates T lymphocytes to inflamed tissues [14], [15] and is produced by fibroblasts, T lymphocytes, monocytes, and endothelial cells [16]. In addition to those cells, we have found that bile acids transcriptionally induced RANTES expression in human hepatoma cells [17]. Thereafter, it is reported that RANTES is induced by TNF-α in T lymphocytes, pulmonary vascular endothelial cells, bronchial epithelial cells, and granuloma cells from human preovulatory follicle [18], [19], [20], [21]. Collectively, several evidences suggest that TNF-α-induced RANTES expression may have a critical role in cell-mediated liver injury associated with alcoholic hepatitis. In fact, immunohistochemical studies of alcoholic cirrhotic livers have indicated that both CD4 and CD8 T lymphocytes can be detected in expanded portal tracts and in periseptal areas associated with interface hepatitis and progressive fibrosis [22].

Fibrates are widely used in the treatment of hyperlipidemia and lower triglyceride levels in patients with hyperlipidemia [23], [24]. Recently, several groups reported that bezafibrate, one of fibrates, is effective in primary biliary cirrhosis treatment [25], [26], [27], [28], [29]. In their reports, bezafibrate is more profitable than ursodeoxycholic acid in patients with primary biliary cirrhosis. 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 [30], [31]. These fibrates promote β-oxidation and suppress acetyl CoA carboxylase activity in the liver [32]. In addition to these pharmacological effects, fibrates activate the peroxisome proliferator-activated receptor (PPAR) α, a member of the nuclear hormone receptor superfamily [33]. These PPARα are reported to be involved in cell proliferation and inflammatory response as well as lipid metabolism [34], [35]. We have also reported that fibrates transcriptionally reduced bile acid-induced RANTES expression in human hepatoma cells, at least in part through inhibition of both DNA-binding activity and transcriptional activation of NF-κB [36]. However, nobody investigated the effects of fibrates on TNF-α-induced RANTES expression in hepatocytes. We, here, presented that bezafibrate and fenofibrate repressed TNF-α-induced RANTES expression in human hepatocyte-derived cells, possibly suggesting that fibrates might be inhibitory agents of migration of inflammatory cells by RANTES to the liver in patients with alcoholic liver diseases.