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 in tercellular adhesion molecule-1 (ICAM-1), as detected by immunohistoch emistry. Up-regulation of ICAM-1 expression on these eels has been rep orted in inflammatory liver disease (hepatitis B virus infection, auto immune liver disorders and liver allograft rejection), and the molecul e has been implicated in the recruitment, retention and activation of inflammatory cells. There is, however, little information concerning t he regulation of hepatocyte expression of ICAM-1. We show here, for th e first time, the induction (within 30 min) of ICAM-1 gene expression in cultured normal human hepatocytes stimulated with interleukin-1 bet a (IL-1 beta), tumour necrosis factor-alpha (TNF-alpha), interferon-ga mma (IFN-gamma) or endotoxin. IFN-gamma was the most potent single ind ucer (up to fourfold at 6 hr), while further induction of ICAM-1 mRNA was achieved with cytokine combinations. Maximal mRNA expression was a chieved within 10 hr. ICAM-1 could be detected readily by immunocytoch emical staining on the hepatocyte surface by 12 hr, and by enzyme immu noassay in the culture medium by 24 hr. The data present clear evidenc e that cytokines, which have been implicated previously in inflammator y liver diseases, can up-regulate directly both ICAM-1 gene expression and protein secretion/shedding by human hepatocytes.