LINOMIDE PREVENTS THE LETHAL EFFECT OF ANTI-FAS ANTIBODY AND REDUCES FAS-MEDIATED CERAMIDE PRODUCTION IN MOUSE HEPATOCYTES

Fas is an apoptosis-signaling receptor molecule expressed in vivo on t hymocytes, liver, heart, and ovary. In vivo administration of the anti -Fas Jo2 antibody in mice induces severe apoptotic liver damage leadin g to fulminant hepatitis and death. Linomide, a quinoline 3-carboxamid e, inhibits apoptosis of B and T cells induced by various stimuli incl uding viruses, superantigens, and glucocorticoids. Mice treated with l inomide survived the lethal effect of anti-Fas antibody, did not accum ulate ceramide in hepatocytes, and recovered liver structure and funct ion within 96 h of anti-Fas injection, as confirmed by histology and g lutamic oxalacetic transaminase, glutamic pyruvic transaminase, and la ctate dehydrogenase levels. Surviving mice showed severe depletion of cortical thymocytes, but medullar thymic cells expressing high CD3 and Fas levels also survived the treatment with anti-Fas in the presence of linomide. Heart, lung, and ovary showed no signs of apoptosis promo ted by Fas ligation. These results suggest that linomide prevents cell death triggered by Fas ligation and can be useful for therapeutic int ervention in fulminant hepatitis.