Proinflammatory cytokines and endotoxin stimulate ICAM-1 gene expression and secretion by normal human hepatocytes

Hepatocytes in normal tissues express low or undetectable levels of intercellular adhesion molecule-1 (ICAM-1), as detected by immunohistochemistry. Up-regulation of ICAM-1 expression on these cells has been reported in inflammatory liver disease (hepatitis B virus infection, autoimmune liver disorders and liver allograft rejection), and the molecule has been implicated in the recruitment, retention and activation of inflammatory cells. There is, however, little information concerning the regulation of hepatocyte expression of ICAM-1. We show here, for the first time, the induction (within 30 min) of ICAM-1 gene expression in cultured normal human hepatocytes stimulated with interleukin-1 beta (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma) or endotoxin. IFN-gamma was the most potent single inducer (up to fourfold at 6 hr), while further induction of ICAM-1 mRNA was achieved with cytokine combinations. Maximal mRNA expression was achieved within 10 hr. ICAM-1 could be detected readily by immunocytochemical staining on the hepatocyte surface by 12 hr, and by enzyme immunoassay in the culture medium by 24 hr. The data present clear evidence that cytokines, which have been implicated previously in inflammatory liver diseases, can up-regulate directly both ICAM-1 gene expression and protein secretion/shedding by human hepatocytes.