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Description and Mapping of the Resistance of DBA/2 Mice to TNF-Induced Lethal Shock¹

Department for Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Ghent, Belgium

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)F₁ mice completely survived an otherwise lethal TNF/IFN--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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. B.W. is a postdoctoral fellow at the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen.

² Current address: Technical University of Dresden, Dresden, Germany.

³ Address correspondence and reprint requests to Dr. Claude Libert, Laboratory of Molecular Biology, Ledeganckstraat 35, Gent, Belgium. E-mail address: Claude.Libert{at}Ugent.be

⁴ Abbreviations used in this paper: SIRS, systemic inflammatory response syndrome; B, C57BL/6; BC, backcross; CS, chromosome substitution; Chr, chromosome; D, DBA/2; IC, intercross; 5-LO, 5-lipoxygenase; LRS, likelihood ratio statistic; MS, multiple sclerosis; QTL, quantitative trait locus; RA, rheumatoid arthritis; SNP, single nucleotide polymorphism.