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

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 singlenucleotide polymorphisms (SNPs; À1082A/G, À819T/C and À592A/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 À592 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.

Dust mite exposure modifies the effect of functional IL10 polymorphisms on allergy and asthma exacerbations

“…Of note, the most consistently replicated genotype-by-dust mite allergen interaction (rs1800896-by-dust antigen level) in our study involves a well described functional variant in IL10. Although many studies have shown decreased IL-10 production associated with the common A allele compared with the G allele of rs1800896, 35,36 others have demonstrated the opposite effect, 23 and 1 study showed no effect. 37 On the basis of these previous studies and our current findings, we speculate that the effect of functional promoter polymorphisms in IL10 on IL-10 transcription by may be complex and linked to the degree of exposure to specific antigenic stimuli (as would be predicted in Fig 1).…”

Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease

“…125 Both factors are implicated in the expression of IL-10 in murine macrophages. 126 In response to apoptotic and perhaps necrotic cells, p38 signaling leads to PBX1 and PREP1 recruitment to a putative apoptotic cell response element (ACRE) in the IL10 promoter that is conserved between human and mouse (163 bp upstream of the translation start site). 126 In this context, IL-10 induction was correlated not with phagocytosis but instead scavenger function, implicating IL-10 in regulating tissue restoration and/or homeostasis.…”

Functional Aspects of PARP1 in DNA Repair and Transcription

“…As an enzyme, PARP1 acts on chromatin remodeling complexes to control DNA accessibility for RNA polymerase [18,19,20,21,22]. PARP1 also functions as a transcription factor by binding an octamer motif in promoter elements to regulate gene expression [23,24,25,26,27,28,29,30]. Interestingly, despite the roles of PARP1 in DNA repair and transcription, little is known about how one process affects the other.…”