The Septic Shock-Associated IL-10 −1082 A > G Polymorphism Mediates Allele-Specific Transcription via Poly(ADP-Ribose) Polymerase 1 in Macrophages Engulfing Apoptotic Cells

Abstract

The biallelic Interleukin-10 single nucleotide polymorphism (SNP) at -1082 of the promoter region linked to individual variation in cytokine inducibility has been strongly implicated in several pathological conditions including the development of, and outcomes in, septic shock during pneumococcal infection, acute respiratory distress syndrome, and cardiac dysfunction. However, the molecular basis of the SNP-mediated variable IL-10 production levels has not been explored. Here we report that the -1082G>A alleles in the promoter region of the human IL-10 gene physically interact with a nuclear protein in an allele-specific manner that results in different levels of IL-10 transcription. This protein has been identified as poly ADP-ribose polymerase 1 (PARP-1). We show that PARP-1 acts as a transcription repressor, and its DNA-binding activity is strongly regulated in macrophages that engulf apoptotic cells but not stimulated with lippopolysaccharides. These findings unveil a novel role of PARP-1 in the regulation of IL-10 production in an allele-dependent way, which determines individual susceptibility to sepsis-induced inflammatory pathology and the immunological sequelae in a physiological process where clearance of infection-induced apoptotic cells by professional phagocytes triggers the cytokine synthesis.

IL10 Promoter Polymorphisms are Associated with Rheumatic Heart Disease in Saudi Arabian Patients

“…In B cells stimulated with lipopolysaccharide, the -1082G allele has a higher affinity than the -1082A allele for the Sp1 transcription factor, which may contribute to increased IL10 production and B cell proliferation [16]. In macrophages stimulated by apoptotic cells, the -1802A allele was shown to have a higher affinity for poly(ADP-ribose)polymerase-1 (PARP1), a transcription factor that suppresses cytokine production and has important functions in systemic inflammation [13]. Macrophages activated by apoptotic cells carrying the -1082G allele would be expected to produce more IL10, which may result in immunological suppression and impaired apoptotic body clearance during acute bacterial infections [33]; this may create a favorable environment for persistent inflammation.…”

Molecular mechanisms of transcriptional regulation by Poly(ADP-ribose) polymerase 1

“…Recognition of the motif depends to a great extent on the nucleotide sequence of its 3' terminal part, especially positions 5 and 6, because mutations in these positions inhibit both tran scription and PARP1 binding. The motif is easily detect able in the promoters of PARP1 regulated genes, includ ing the genes for the immune regulators interferon γ [99] and interleukin 10 [100]; target genes regulated in virus infection, such as infection with the human T cell leuke mia virus (HTLV) [101]; and the gene for BRCA2 [102]. The promoters of DNA repair genes also often contain PARP1 binding DNA sequences, which occur within 3 kb of the transcription start site (table).…”

“…Thus many PARP1 involving dis orders develop independently of ADP ribosylating activity of PARP1, being rather associated with a dys regulation of PARP1 synthesis or changes in PARP1 affinity for its binding sites in chromatin. For instance, a specific binding of PARP1 to the promoters of the genes for the cytokine IL 10 [100], chemokine CCL [115], interferon α/β receptor 1 (INFAR1) [103], and SMARCB1 [104] genes is improved in systemic lupus At the same time, both of the PARP1 functions (in DNA repair and transcription) are modified as a result of PARP1 activity inhibition in certain diseases. In diabetes mellitus, PARP inhibitors may provide a ther apeutic benefit because inhibition of ADP ribosyla tion suppresses inflammation and improves the effi ciency of PARP1 dependent transcription of Reg, which is necessary for β cell regeneration [116].…”

Evidence-guided optimization of herbal formula Cheong-Hwa-Bo-Um-Tang using multiplex cytokine profiling

“…But the uncontrolled inflammatory phenomena could be a turning point for the development of acute or chronic inflammatory diseases (dos Santos et al, 2012). Among the many immuno-inflammatory leukocytes, macrophages and monocytes are of great importance (Kang et al, 2010).…”