International Mammalian Genome Society

17th International Mouse Genome Conference

9-12 November 2003, Braunschweig, Germany


POSTER 184 - FURTHER RESEARCH OF THE RESISTANCE OF SPRET/EI TO TNF INDUCED LETHAL SHOCK

Staelens J
Unit for Molecular Genetics of the Mouse, Department of Molecular Biomedical Research, VIB/RUG, Ghent, Belgium

Co-Authors: Vandenabeele A, Wielockx B, Puimège L, Hochepied T, Van Molle W, Affenas A, Van Roy F, Libert C
Institutions: Unit for Molecular Genetics of the Mouse, Department of Molecular Biomedical Research, VIB/RUG, Ghent, Belgium

Tumor Necrosis Factor (TNF) is a cytokine with a potent antitumor activity. TNF is able to specifically regress tumors 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, bowel necrosis, 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 and sepsis.

We have previously shown that SPRET/Ei mice (an inbred strain derived from the species Mus spretus) and (C57BL/6xSPRET/Ei)F1 mice, in contrast to C57BL/6 mice, display an extreme resistance to TNF induced lethal shock and to TNF induced gene expression (e.g. of the IL-6 gene) (1). Thanks to this phenotype, tumor-bearing (C57BL/6xSPRET/Ei)F1 mice can be successfully treated using TNF and IFNγ, resulting in tumor regression but much reduced toxicity. Using an interspecies backcross, we have shown that loci conferring resistance to TNF are located on distal chromosome 6 and proximal chromosome 2. A locus conferring sensitivity is located on distal chromosome 11.

In the current study, we have performed a more detailed analysis of in vivo signalling after TNF injection in SPRET/Ei compared to C57BL/6. Iκ -Bα degradation, and hence NF-κ B translocation, seems to occur as efficiently in SPRET/Ei and (C57BL/6xSPRET/Ei)F1 as in C57BL/6. However there seems to be less ERK and JNK activation in SPRET/Ei and (C57BL/6xSPRET/Ei)F1 compared toC57BL/6. Inhibition of glucocorticoid signalling (by adrenolectomy or using the glucocorticoid receptor blocker RU486) sensitizes C57BL/6, but also (C57BL/6xSPRET/Ei)F1 to the toxic effects of TNF, suggesting a role for glucocorticoids in the TNF resistance. However, (C57BL/6xSPRET/Ei)F1 still display a mild resistance compared to C57BL/6 towards TNF/RU486 toxicity.

Based upon the mappositions obtained, two obvious candidate genes, the tnfrsf1a-gene (chromosome 6) coding for the TNF receptor 1 and the traf2-gene (chromosome 2) coding for the TNF receptor associated factor 2 were sequenced. In both genes, mutations were found in SPRET/Ei. The significance of these mutations remains to be determined in a biological assay.


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