International Mammalian Genome Society

The 15th International Mouse Genome Conference (2001)

POSTER 53 - Mapping and cloning of TNF resistance genes in Mus spretus.

Mr. Jan Staelens
Department of Molecular Biology
K.L.Ledeganckstraat 35
9000 Ghent

Co-Authors: 1) Staelens J, 1) Wielockx B, 1) Hochepied T, 1) Van Molle W, 2) Gunet JL, 1) Van Roy F, 1) Libert C.
Institutions: 1)Department of Molecular Biology, VIB/RUG, 2)Institut Pasteur

Tumor Necrosis Factor (TNF) is a cytokine with a potent antitumor activity. TNF is able to specifically kill tumor cells in vivo with high efficiency. TNF is also a pro-inflammatory cytokine. Injection of TNF in patients or experimental animals induces a Systemic Inflammatory Response Syndrome, resulting in hypotension, multiple organ failure, liver damage and ultimately death. The use of TNF has therefore been limited to local treatment of tumors. TNF is also centrally involved in a number of diseases such as rheumatoid arthritis, inflammatory bowel disease, asthma, MS, sepsis, We have tested the response of several mouse inbred strains to TNF and identified several strains that showed a hyporesponsiveness to TNF. The most resistant strain we identified was SPRET/Ei, an inbred strain from the species Mus spretus. SPRET/Ei mice were resistant to up to 500 g TNF while C57BL/6 mice (Mus musculus) succumbed to 25 g TNF. All TNF-induced changes in parameters were also much reduced in SPRET/Ei. The trait was dominant since (BxS)F1 mice were equally resistant to TNF as SPRET/Ei. To map the TNF resistance genes, we performed an interspecies backcross. 130 (BxS)F1xB mice were injected with a dose of TNF, lethal to C57BL/6 but not to SPRET/Ei and lethality was scored. A genome wide screen was performed and showed that TNF resistance was linked to loci on chromosomes 2 and 6. We also identified two SPRET-derived sensitivity loci on chromosomes 7 and 11.

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