MICE HETEROZYGOUS FOR A DELETION OF THE TUMOR-NECROSIS-FACTOR-ALPHA AND LYMPHOTOXIN-ALPHA GENES - BIOLOGICAL IMPORTANCE OF A NONLINEAR RESPONSE OF TUMOR-NECROSIS-FACTOR-ALPHA TO GENE DOSAGE

The tumor necrosis factors (TNF-alpha and lymphotoxin, or LT-alpha) ar e important mediators of the immune and inflammatory responses, and it has been proposed that a positive feedback loop could boost the expre ssion of the TNF to sufficiently high levels to fend off infections. T o investigate this phenomenon and its biological consequences, we have generated LT-alpha/TNF-alpha knockout mice and compared mice having o ne or two functional LT-alpha/TNF-alpha alleles. In response to lipopo lysaccharide (LPS) stimulation, TNF-alpha 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 dif ferential increased with the intensity of stimulation and throughout t he response, supporting the involvement of a positive feedback loop. M oreover, the heterozygous mice had an increased bacterial load followi ng Listeria monocytogenes infection and exhibited a bimodal response t o 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 homozygou s mutants at high doses. These results therefore establish the biologi cal importance of the nonlinear response of TNF-alpha levels to gene d osage, and these mice provide a unique tool to study how the propensit y to produce TNF can determine the immunological fitness of individual s.