期刊
JOURNAL OF IMMUNOLOGY
卷 186, 期 4, 页码 2329-2335出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1002402
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资金
- Wellcome Trust [068026, 078857/Z/05/Z]
- Alder Hey Children's National Health Service Foundation Trust [7565]
- National Institute of Health Research Liverpool Biomedical Research Centre for Microbial Diseases
- Wellcome Trust [078857/Z/05/Z] Funding Source: Wellcome Trust
IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased similar to 6-fold as compared with basal activity, and that containing the C allele by similar to 9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections. The Journal of Immunology, 2011, 186: 2329-2335.
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