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.
Eur J Immunol
; 27(4): 1035-42, 1997 Apr.
Article
en En
| MEDLINE
| ID: mdl-9130661
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.
Buscar en Google
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Linfotoxina-alfa
/
Factor de Necrosis Tumoral alfa
/
Eliminación de Gen
/
Dosificación de Gen
/
Heterocigoto
Límite:
Animals
Idioma:
En
Revista:
Eur J Immunol
Año:
1997
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Alemania