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To investigate this phenomenon and its biological consequences, we have generated LT\u2010\u03b1\/TNF\u2010\u03b1 knockout mice and compared mice having one or two functional LT\u2010\u03b1\/TNF\u2010\u03b1 alleles. In response to lipopolysaccharide (LPS) stimulation, TNF\u2010\u03b1 levels in the circulation or in the supernatant of macrophage cultures were 20\u2010 to 100\u2010fold lower in heterozygous samples than in their wild\u2010type counterparts. This differential increased with the intensity of stimulation and throughout the response, supporting the involvement of a positive feedback loop. Moreover, the heterozygous mice had an increased bacterial load following <jats:italic>Listeria monocytogenes<\/jats:italic> infection and exhibited a bimodal response to the association of <jats:sc>D<\/jats:sc>\u2010galactosamine and LPS which was similar to that of wild\u2010type mice at low doses of LPS and more like that of homozygous mutants at high doses. These results therefore establish the biological importance of the nonlinear response of TNF\u2010\u03b1 levels to gene dosage, and these mice provide a unique tool to study how the propensity to produce TNF can determine the immunological fitness of individuals.<\/jats:p>","DOI":"10.1002\/eji.1830270434","type":"journal-article","created":{"date-parts":[[2007,3,2]],"date-time":"2007-03-02T04:32:40Z","timestamp":1172809960000},"page":"1035-1042","source":"Crossref","is-referenced-by-count":37,"title":["Mice heterozygous for a deletion of the tumor necrosis factor\u2010\u03b1 and lymphotoxin\u2010\u03b1 genes: biological importance of a nonlinear response of tumor necrosis factor\u2010\u03b1 to gene dosage"],"prefix":"10.1002","volume":"27","author":[{"given":"Franck","family":"Amiot","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Or\u00e9da","family":"Boussadia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylvaine","family":"Cases","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Fitting","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mai","family":"Lebastard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010Marc","family":"Cavaillon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevi\u00e8ve","family":"Milon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Dautry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,12,6]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.10.040192.002211"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90134-C"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/364798a0"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/8.1.23"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.89.11.4864"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.171.1.327"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/346274a0"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00215292"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.8171322"},{"key":"e_1_2_1_11_2","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.4049\/jimmunol.155.4.1685","volume":"155","author":"Banks T. 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