For COVID-19 vaccine updates, please review our information guide. For patient eligibility and scheduling availability, please visit VaccineTogetherNY.org.

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.

TitleThe septic shock-associated IL-10 -1082 A > G polymorphism mediates allele-specific transcription via poly(ADP-Ribose) polymerase 1 in macrophages engulfing apoptotic cells.
Publication TypeJournal Article
Year of Publication2010
AuthorsKang X, Kim H-J, Ramirez M, Salameh S, Ma X
JournalJ Immunol
Volume184
Issue7
Pagination3718-24
Date Published2010 Apr 01
ISSN1550-6606
KeywordsAlleles, Animals, Apoptosis, Electrophoresis, Polyacrylamide Gel, Electrophoretic Mobility Shift Assay, Genetic Predisposition to Disease, Humans, Interleukin-10, Jurkat Cells, Macrophages, Mice, Oligonucleotide Array Sequence Analysis, Phagocytosis, Poly (ADP-Ribose) Polymerase-1, Poly(ADP-ribose) Polymerases, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Shock, Septic, Transcription, Genetic, Transfection
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.

DOI10.4049/jimmunol.0903613
Alternate JournalJ Immunol
PubMed ID20181890
PubMed Central IDPMC3637664
Grant ListR01 AI045899 / AI / NIAID NIH HHS / United States

Weill Cornell Medicine Microbiology and Immunology 1300 York Avenue, Box 62 New York, NY 10065 Phone: (212) 746-6505 Fax: (212) 746-8587