Description and mapping of the resistance of DBA/2 mice to TNF-induced lethal shock.
In our search for genes that inhibit the inflammatory effects of TNF without diminishing its antitumor capacities we found that, compared with C57BL/6 mice, DBA/2 mice exhibit a dominant resistance to TNF-induced lethality. Tumor-bearing (C57BL/6 x DBA/2)(BXD)F(1) mice completely survived an otherwise lethal TNF/IFN-gamma-antitumor therapy with complete regression of the tumor. This was not the case for C57BL/6 mice. Genetic linkage analysis revealed that TNF resistance is linked to a major locus on distal chromosome 6 and a minor locus on chromosome 17. Compared with littermate controls, chromosome substitution mice carrying a DBA/2 chromosome 6 in a C57BL/6 background were significantly protected against TNF and TNF/IFN-gamma, albeit less so than DBA/2 mice. Definition of a critical region of 13 Mb on chromosome 6 was the highest mapping resolution obtained. Further analysis of candidate genes may provide a powerful tool to control TNF-induced pathologies in humans.
Wielockx
Ben
B
Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Ghent, Belgium.
Staelens
Jan
J
Puimège
Leen
L
Vanlaere
Ineke
I
Van Roy
Maarten
M
van Lint
Philippe
P
Van Roy
Frans
F
Libert
Claude
C
D000818:Animals; D002874:Chromosome Mapping; D005260:Female; D007371:Interferon-gamma / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D040641:Quantitative Trait Loci; D012769:Shock / Q000139:chemically induced*; D013045:Species Specificity; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000633:toxicity*
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma