Differential expression in lupus-associated IL-10 promoter single-nucleotide polymorphisms is mediated by poly(ADP-ribose) polymerase-1.
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.
Chung
E Y
EY
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
Liu
J
J
Zhang
Y
Y
Ma
X
X
D000483:Alleles; D000818:Animals; D017209:Apoptosis; D005838:Genotype; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D010587:Phagocytosis; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic
D008070:Lipopolysaccharides; D016753:Interleukin-10; D011065:Poly(ADP-ribose) Polymerases