Mice heterozygous for a deletion of the tumor necrosis factor‐α and lymphotoxin‐α genes: biological importance of a nonlinear response of tumor necrosis factor‐α to gene dosage

Abstract

The tumor necrosis factors (TNF‐α and lymphotoxin, or LT‐α) are important mediators of the immune and inflammatory responses, and it has been proposed that a positive feedback loop could boost the expression of the TNF to sufficiently high levels to fend off infections. To investigate this phenomenon and its biological consequences, we have generated LT‐α/TNF‐α knockout mice and compared mice having one or two functional LT‐α/TNF‐α alleles. In response to lipopolysaccharide (LPS) stimulation, TNF‐α levels in the circulation or in the supernatant of macrophage cultures were 20‐ to 100‐fold lower in heterozygous samples than in their wild‐type counterparts. This differential increased with the intensity of stimulation and throughout the response, supporting the involvement of a positive feedback loop. Moreover, the heterozygous mice had an increased bacterial load following Listeria monocytogenes infection and exhibited a bimodal response to the association of D‐galactosamine and LPS which was similar to that of wild‐type mice at low doses of LPS and more like that of homozygous mutants at high doses. These results therefore establish the biological importance of the nonlinear response of TNF‐α levels to gene dosage, and these mice provide a unique tool to study how the propensity to produce TNF can determine the immunological fitness of individuals.