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) 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-alpha/TNF-alpha knockout mice and compared mice having one or two functional LT-alpha/TNF-alpha alleles. In response to lipopolysaccharide (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 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-alpha 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.
Amiot
F
F
Génétique Moléculaire et Intégration des Fonctions Cellulaires, CNRS UPR 9044, Institut de Recherches sur le Cancer, Villejuif, France.
Boussadia
O
O
Cases
S
S
Fitting
C
C
Lebastard
M
M
Cavaillon
J M
JM
Milon
G
G
Dautry
F
F
D000483:Alleles; D000818:Animals; D002478:Cells, Cultured; D004198:Disease Susceptibility; D005688:Galactosamine / Q000633:toxicity; D017353:Gene Deletion; D018628:Gene Dosage; D006579:Heterozygote; D007275:Injections, Intravenous; D008070:Lipopolysaccharides / Q000633:toxicity; D008088:Listeriosis / Q000235:genetics / Q000276:immunology / Q000401:mortality; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*
D008070:Lipopolysaccharides; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha; D005688:Galactosamine