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

Genes & Immunity volume 8, pages 577–589 (2007)Cite this article

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.

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Acknowledgements

This work was supported by a grant from the NIH (AI45899) to XM and a grant from the Mary Kirkland Foundation for Lupus Research to XM.

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  1. E Y Chung and J Liu: These individuals are considered co-first authors.

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  1. Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA

    E Y Chung, J Liu, Y Zhang & X Ma

  2. Graduate Program in Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences, Cornell University, New York, NY, USA

    E Y Chung & X Ma

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Chung, E., Liu, J., Zhang, Y. et al. Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1. Genes Immun 8, 577–589 (2007). https://doi.org/10.1038/sj.gene.6364420

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