| First Author | Libert C | Year | 1999 |
| Journal | Genomics | Volume | 55 |
| Issue | 3 | Pages | 284-9 |
| PubMed ID | 10049582 | Mgi Jnum | J:53210 |
| Mgi Id | MGI:1331521 | Doi | 10.1006/geno.1998.5677 |
| Citation | Libert C, et al. (1999) Identification of a locus on distal mouse chromosome 12 that controls resistance to tumor necrosis factor-induced lethal shock. Genomics 55(3):284-9 |
| abstractText | Administration of recombinant murine tumor necrosis factor (TNF) to mice results in lethal shock, characterized by hypotension, hypothermia, and dramatic induction of cytokines released in the circulation, such as interleukin-6 (IL-6). The sensitivity of mice to the effects of murine TNF varies from strain to strain. DBA/2 mice were found to be considerably more resistant to TNF than C57BL/6 mice. The resistance proved to be dominant since (C57BL/6 x DBA/2)F1 mice were also resistant. Using BXD recombinant inbred mice and a dose of TNF lethal for C57BL/6 but not for DBA/2 mice, we found that the resistance to TNF links to loci coding for corticosteroid-binding globulin (Cbg), alpha1-protease inhibitor (Spi1), contrapsin (Spi2) and the contrapsin-regulating gene Spi2r that form a gene cluster on chromosome 12. Quantitative trait-loci analysis of TNF-induced induction of IL-6 and of hypothermia also points to the importance of this locus (P < 0.0002 and P = 0.017, respectively), more particularly the Cbg and Spi2 loci, in the resistance to TNF. We propose to name the locus 'TNF protection locus.' The data suggest that endogenous protease inhibitors and/or glucocorticoids play a significant role in the attenuation of TNF-induced lethal shock. This study also demonstrates that loci affecting important biological responses can be identified with very high resolution using recombinant inbred mice. |
