Accelerated publication - Bile acid induction of cytokine expression by macrophages correlates with repression of hepatic cholesterol 7 alpha-hydroxylase

In the studies reported herein, we show that two complementary experimental models: inbred strains of mice (i.e. C57BL/6 and C3H/HeJ), and a different iated line of rat hepatoma cells (i.e. L35 cells), require the activation o f cytokines by monocyte/macrophages to display bile acid negative feedback repression of cholesterol 7 alpha-hydroxylase (CYP7A1), Feeding a bile acid -containing atherogenic diet for 3 weeks to C57BL/6 mice led to a 70% reduc tion in the expression of hepatic CYP7A1 mRNA whereas no reduction was obse rved in C3H/HeJ mice. The strain-specific response to repression of CYP7A1 paralleled the activation of hepatic cytokine expression. Studies using cul tured THP-1 monocyte/macrophages showed that the hydrophobic bile acid chen odeoxycholate, a well established potent repressor of CYP7A1, induced the e xpression of mRNAs encoding interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF alpha), In contrast, the hydrophilic bile acid ursodeoxycholate, which does not repress CYP7A1, did not induce cytokine mRNA expression by THP-1 cells. Chenodeoxycholate activation of cytokines by THP-1 cells was b locked by the peroxisome proliferator-activated receptor gamma agonist rosi glitazone. The expression of cytokines (e.g. IL-1 and TNF alpha) by THP-1 c ells paralleled with the ability of these cells to produce conditioned medi um that when added to rat L35 hepatoma cells, repressed CYP7A1. Moreover, r osiglitazone, which blocks cytokine activation by macrophages, also blocked the repression of CYP7A1 normally exhibited by C57BL/6 mice fed the bile a cid-containing atherogenic diet. The combined data indicate that the activa tion of cytokines may mediate CYP7A1 repression caused by feeding mice an a therogenic diet containing bile acids.