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Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1.

TitleDifferential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1.
Publication TypeJournal Article
Year of Publication2007
AuthorsChung EY, Liu J, Zhang Y, Ma X
JournalGenes Immun
Volume8
Issue7
Pagination577-89
Date Published2007 Oct
ISSN1466-4879
KeywordsAlleles, Animals, Apoptosis, Genotype, Haplotypes, Homozygote, Humans, Interleukin-10, Lipopolysaccharides, Lupus Erythematosus, Systemic, Macrophages, Peritoneal, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Phagocytosis, Poly(ADP-ribose) Polymerases, Polymorphism, Single Nucleotide, Promoter Regions, Genetic
Abstract

Systemic lupus erythematosus (SLE) is a complex, multifactorial autoimmune disease characterized by the dysregulation of T and B cells that leads to hyperactivity of B cells and production of autoantibodies, and involves both environmental and genetic factors. Interleukin-10 (IL-10) is a candidate susceptibility gene in SLE. In particular, three IL-10 promoter single-nucleotide polymorphisms (SNPs; -1082A/G, -819T/C and -592A/C) are strongly associated with the pathogenesis of SLE. We found that the homozygous GCC haplotype linked to greater SLE severity confers higher IL-10 gene transcriptional activity than the ATA haplotype in macrophages that encounter apoptotic cells, because of the differential DNA binding to the -592 SNP by a nuclear protein uniquely induced by apoptotic cells. We identified this protein as poly(ADP-ribose) polymerase-1, confirmed its physiological role and characterized its molecular properties in modulating IL-10 production during phagocytosis of apoptotic cells. This study unveils a novel direct link between DNA damage repair/apoptosis pathways and IL-10-mediated immune regulation.

DOI10.1038/sj.gene.6364420
Alternate JournalGenes Immun
PubMed ID17703177
Grant ListAI45899 / AI / NIAID NIH HHS / United States

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