CIRCULATING INTERCELLULAR-ADHESION MOLECULE-1 (ICAM-1) IN AUTOIMMUNE LIVER-DISEASE AND EVIDENCE FOR THE PRODUCTION OF ICAM-1 BY CYTOKINE-STIMULATED HUMAN HEPATOCYTES

A circulating form of the membrane-bound ICAM-1 (CD54), a ligand for l ymphocyte function-associated antigen-1 (LFA-1), has recently been ide ntified in normal human serum. In this study, serum levels of soluble ICAM-1 (sICAM-1) were determined by sandwich ELISA both in normal heal thy individuals of both sexes and in subjects with autoimmune liver di seases. Patients with primary biliary cirrhosis (PBC), primary scleros ing cholangitis and chronic active hepatitis (autoimmune) showed signi ficant elevations in sICAM-1 compared with normal healthy subjects. Th e median level in PBC was approximately seven-fold above normal. Signi ficant elevations in sICAM-1 were also detected, however, in patients with inactive alcoholic cirrhosis, suggesting that impaired liver clea rance might at least in part account for the increased serum levels se en in patients with autoimmune liver disease. In patients with PBC, sI CAM-1 levels were related to summary assessment of disease severity (C hild-Pugh classification) and correlated significantly with serum bioc hemical indices of liver function, including measures both of cholesta sis and liver cell injury. In contrast, serum levels of E-selectin did not differ significantly from healthy controls. Although it has been suggested that peripheral blood mononuclear cells (PBMC) may be a sour ce of sICAM-1, investigation of ICAM-1 gene expression by reverse tran scriptase polymerase chain reaction revealed similar basal levels of I CAM-1 message in PBMC of normal individuals and those with active PBC. This suggests that PBMC may not be a significant source of sICAM-1 in this disease. Similar increases in ICAM-1 mRNA expression were found in cultured, concanavalin A (Con A)-stimulated lymphocytes of both PBC patients and controls. Significantly, stimulation of cultured, normal human hepatocytes with proinflammatory cytokines and endotoxin induce d cell surface expression of ICAM-1 and the secretion/shedding of sICA M-1 into the hepatocyte culture medium. This new finding suggests that hepatocytes may be an important source of sICAM-1 in autoimmune and o ther chronic liver diseases. The possible role of sICAM-1 in inflammat ory disorders remains to be determined.