MICE LACKING THE TUMOR-NECROSIS-FACTOR RECEPTOR-1 ARE RESISTANT TO TNF-MEDIATED TOXICITY BUT HIGHLY SUSCEPTIBLE TO INFECTION BY LISTERIA-MONOCYTOGENES

TUMOUR necrosis factor (TNF), jointly referring to TNFalpha and TNFbet a, is a central mediator of immune and inflammatory responses; its act ivities are mediated by two distinct receptors, TNFR1 (p55) and TNFR2 (p75) (reviewed in refs 1-3). The cytoplasmic domains of the TNFRs are unrelated, suggesting that they link to different intracellular signa lling pathways4. Although most TNF responses have been assigned to one or the other of the TNF receptors (mostly TNFR1), there is no general ly accepted model for the physiological role of the two receptor types . To investigate the role of TNFR1 in beneficial and detrimental activ ities of TNF, we generated TNFR1-deficient mice by gene targeting. We report here that mice homozygous for a disrupted Tnfr1 allele (Tnfr1(0 )) are resistant to the lethal effect of low doses of lipopolysacchari de after sensitization with D-galactosamine, but remain sensitive to h igh doses of lipopolysaccharide. The increased susceptibility of Tnfr1 (0)/Tnfr1(0) mutant mice to infection with the facultative intracellul ar bacterium Listeria monocytogenes indicates an essential role of TNF in nonspecific immunity.