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Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9016-20. doi: 10.1073/pnas.0813362106. Epub 2009 May 15.

Gender differences in expression of the human caspase-12 long variant determines susceptibility to Listeria monocytogenes infection.

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1
Department of Medicine, Centre for the Study of Host Resistance and Complex Trait Group, McGill University, Montreal, QC, Canada H3G 0B1.

Abstract

Inflammatory caspases are important effectors of innate immunity. Caspase-12, 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 caspase-12 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 casp-12(-/-) background. Characterization of the humanized mouse uncovered sex differences in Csp-12L expression and gender disparity in innate immunity to Listeria monocytogenes infection. The Csp-12L transgene completely reversed the knockout resistance-to-infection phenotype in casp-12(-/-) 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-beta-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 caspase-12 is a direct transcriptional target of the estrogen receptor alpha (ERalpha) 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.

PMID:
19447924
PMCID:
PMC2690057
DOI:
10.1073/pnas.0813362106
[Indexed for MEDLINE]
Free PMC Article
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