PHENOTYPIC ANALYSIS OF TNFR1-DEFICIENT MICE AND CHARACTERIZATION OF TNFR1-DEFICIENT FIBROBLASTS IN-VITRO

In order to analyse the physiological relevance of the 55 kDa tumor ne crosis factor receptor 1 (TNFR1) and its role in various TNF related p athological conditions, such as septic shock, we have generated mice b y gene targeting deficient for TNFR1 expression. The TNFR1-deficient m ice are unable to cope with Listeria monocytogenes infections but moun t an apparently normal immune response when challenged with Vaccinia o r LCMV viruses. They are resistant to the lethal effects of lipopolysa ccharide (LPS) after sensitization with D-galactosamine (D-GalN) but r emain sensitive to very high doses of LPS given alone. We have analyze d functions relevant to inflammatory processes, such as adhesion, seco ndary factor release, and proliferation in fibroblasts derived from th ese mice. We show that the TNFR1 virtually monopolises TNF-mediated si gnaling in all these situations and that the 75 kDa TNFR2 seems to be largely restricted to an accessory role, which is compatible with the previously established ''ligand passing'' hypothesis. (C) 1995 Wiley-L iss, Inc.