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 IL-10 single nucleotide polymorphism 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 single nucleotide polymorphism-mediated variable IL-10 production levels has not been explored. In this study, 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 LPS. 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 in which clearance of infection-induced apoptotic cells by professional phagocytes triggers the cytokine synthesis.