Bile Acids Increase Proinflammatory Gene Expression In Mouse Hepatocytes By Early Growth Response Factor-1-Dependent Mechanisms

Cholestasis results when excretion of bile acids from the liver is interrupted. Recent studies have shown that inflammation is required for liver injury that occurs during cholestasis. Data from our laboratory has shown that early growth response factor‐1 (Egr‐1) knockout mice express lower levels of the proinflammatory mediators, such as intercellular adhesion molecule‐1 (ICAM‐1) and macrophage inflammatory protein‐2 (MIP‐2) in liver after bile duct ligation, and that Egr‐1 is upregulated in hepatocytes exposed to bile acids in vitro . However, it is not known whether ICAM‐1 and MIP‐2 are increased in hepatocytes after bile acid exposure, and whether this occurs by Egr‐1‐dependent mechanisms. Accordingly, we tested the hypothesis that bile acids upregulate ICAM‐1 and MIP‐2 in hepatocytes by Egr‐1‐dependent mechanisms. To test this hypothesis, hepatocytes were isolated from wild‐type and Egr‐1 knockout mice, and exposed to bile acids. ICAM‐1 and MIP‐2 mRNAs were upregulated in wild‐type hepatocytes exposed to deoxycholic acid, chenodeoxycholic acid and taurocholic acid. Upregulation of both ICAM‐1 and MIP‐2 was attenuated in hepatocytes isolated from Egr‐1 knockout mice. These data suggest that the proinflammatroy mediators, ICAM‐1 and MIP‐2, are increased in hepatocytes by bile acids in an Egr‐1‐dependent manner.