{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:33:49Z","timestamp":1791297229170,"version":"4.1.0"},"reference-count":26,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2009,6,2]]},"abstract":"<jats:p>\n                    Inflammatory caspases are important effectors of innate immunity.\n                    <jats:italic>Caspase-12<\/jats:italic>\n                    , of the inflammatory caspase subfamily, is expressed in all mammals tested to date, but has acquired deleterious mutation in humans. A single-nucleotide polymorphism introduces a premature stop codon in\n                    <jats:italic>caspase-12<\/jats:italic>\n                    in the majority of the population. However, in 20% of African descendants, caspase-12 is expressed and sensitizes to infections and sepsis. Here, we examined the modalities by which human caspase-12 confers susceptibility to infection. We have generated a fully humanized mouse that expresses the human caspase-12 rare variant (Csp-12L) in a mouse\n                    <jats:italic>casp-12<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    background. Characterization of the humanized mouse uncovered sex differences in Csp-12L expression and gender disparity in innate immunity to\n                    <jats:italic>Listeria monocytogenes<\/jats:italic>\n                    infection. The Csp-12L transgene completely reversed the knockout resistance-to-infection phenotype in\n                    <jats:italic>casp-12<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    males. In contrast, it had a marginal effect on the response of female mice. We found that estrogen levels modulated the expression of caspase-12. Csp-12L was expressed in male mice but its expression was repressed in female mice. Administration of 17-\u03b2-estradiol (E2) to humanized male mice had a direct suppressive effect on Csp-12L expression and conferred relative resistance to infection. Chromatin immunoprecipitation experiments revealed that\n                    <jats:italic>caspase-12<\/jats:italic>\n                    is a direct transcriptional target of the estrogen receptor alpha (ER\u03b1) and mapped the estrogen response element (ERE) to intron 7 of the gene. We propose that estrogen-mediated inhibition of Csp-12L expression is a built-in mechanism that has evolved to protect females from infection.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0813362106","type":"journal-article","created":{"date-parts":[[2009,5,15]],"date-time":"2009-05-15T21:10:52Z","timestamp":1242421852000},"page":"9016-9020","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":58,"title":["Gender differences in expression of the human caspase-12 long variant determines susceptibility to\n                    <i>Listeria monocytogenes<\/i>\n                    infection"],"prefix":"10.1073","volume":"106","author":[{"given":"Garabet","family":"Yeretssian","sequence":"first","affiliation":[{"name":"Department of Medicine, Centre for the Study of Host Resistance and Complex Trait Group, McGill University, Montreal, QC, Canada H3G 0B1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karine","family":"Doiron","sequence":"additional","affiliation":[{"name":"Department of Medicine, Centre for the Study of Host Resistance and Complex Trait Group, McGill University, Montreal, QC, Canada H3G 0B1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Medicine, Centre for the Study of Host Resistance and Complex Trait Group, McGill University, Montreal, QC, Canada H3G 0B1;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blair R.","family":"Leavitt","sequence":"additional","affiliation":[{"name":"Centre of Molecular Medicine and Therapeutics, Vancouver, BC, Canada V5Z 4H4; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Hayden","sequence":"additional","affiliation":[{"name":"Centre of Molecular Medicine and Therapeutics, Vancouver, BC, Canada V5Z 4H4; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald W.","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Merck Research Laboratories, Rahway, NJ 07065-0900"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Saleh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Centre for the Study of Host Resistance and Complex Trait Group, McGill University, Montreal, QC, Canada H3G 0B1;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2009,6,2]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2007.09.002"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708182200"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020506300324"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2007.12.040"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(00)01936-3"},{"key":"e_1_3_3_6_2","first-page":"380","article-title":"Cell death in the host response to pathogens","volume":"43","author":"Labb\u00e9 K","year":"2008","unstructured":"K Labb\u00e9, M Saleh, Cell death in the host response to pathogens. Cell Death Differ 43, 380\u2013390 (2008).","journal-title":"Cell Death Differ"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(02)00599-3"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80943-5"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04656"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(02)00289-9"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature02451"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1086\/503116"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.169.7.3869"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.176.1.484"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.180.11.7558"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.0040006"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-127-32768"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0899-5885(02)00028-X"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1989.03420090077035"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.73.9.5952-5960.2005"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601977"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.76.050106.093909"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200303157"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.7638587"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568010043483944"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1901"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0813362106","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T18:22:06Z","timestamp":1649787726000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0813362106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,6,2]]},"references-count":26,"journal-issue":{"issue":"22","published-print":{"date-parts":[[2009,6,2]]}},"alternative-id":["10.1073\/pnas.0813362106"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0813362106","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1161733.623325","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,6,2]]},"assertion":[{"value":"2009-01-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2009-06-02","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}