ALTERATION IN MESSENGER-RNA LEVELS OF FAS SPLICE VARIANTS IN HEPATITIS C-INFECTED LIVER

The Fas receptor (APO-1/CD95) is expressed on hepatocytes and is thoug ht to be important in triggering apoptosis after ligation by the Fas l igand carried on cytotoxic T cells. Recent evidence has shown that sev eral splice variants of Fas exist, the major one of which (FasTMDel) m ay produce a soluble protein which can modulate apoptosis by interacti ng with ligand. There are no data on the expression of splice variants of Fas in liver disease, RNA was extracted from needle biopsies from 13 patients with hepatitis C virus (HCV) infection and six normal live r samples, By reverse transcriptase polymerase chain reaction (RT-PCR) FasTMDel expression was demonstrated at the mRNA level, in both norma l and HCV-infected liver, Quantitative PCR demonstrated an increase in Fas transcript relative to FasTMDel in HCV infection, This difference is due to an induction of Fas, with FasTMDel remaining at constant le vels in the two groups. If translated into protein, liver cells may ex press more Fas and thus be susceptible to apoptosis inducible by ligan d-bearing cytotoxic T cells, These findings suggest that mechanisms ex ist to regulate the differential splicing of Fas and FasTMDel dependen t on the cell's environment, The degree of alteration in the levels of Fas relative to FasTMDel occurred independently of the ALT levels and histological grading of the HCV-infected cases. However, an associati on was noted between increasing Fas:FasTMDel ratio and log viral load in the liver, measured by competitive PCR. (C) 1997 John Wiley & Sons, Ltd.