Nature 364, 798 - 802 (26 August 1993); doi:10.1038/364798a0

Mice lacking the tumour necrosis factor receptor 1 are resistant to IMF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes

Joachim Rothe^*†, Werner Lesslauer^*, Hansruedi Lötscher^*, Yolande Lang^*, Pascale Koebel^*, Frank Köntgen^*†, Alana Althage^‡, Rolf Zinkernagel^‡, Michael Steinmetz^*† & Horst Bluethmann^*§

^*Department of Biology, Pharmaceutical Research New Technologies, Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland
^‡Institute of Experimental Immunology University of Zürich, CH-8057 Zürich, Switzerland
^†Present addresses: Imperial Cancer Research Fund, Genome Analysis Laboratory, Lincoln's Inn Fields 44, London WC2A 3PX, UK (J.R.); The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia (F.K.); Preclinical Research, F. Hoffmann-La Roche Inc., Nutley, New Jersey 07110, USA (M.S.).
^§To whom correspondence should be addressed.

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

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