Journal article
Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses
The Journal of immunology (1950), Vol.192(5), pp.2326-2338
03/01/2014
DOI: 10.4049/jimmunol.1301758
PMCID: PMC3943971
PMID: 24477906
Abstract
Macrophages, including alveolar macrophages, are primary phagocytic cells of the innate immune system. Many studies of macrophages and inflammation have been done in mouse models, in which inducible NO synthase (NOS2) and NO are important components of the inflammatory response. Human macrophages, in contrast to mouse macrophages, express little detectable NOS2 and generate little NO in response to potent inflammatory stimuli. The human NOS2 gene is highly methylated around the NOS2 transcription start site. In contrast, mouse macrophages contain unmethylated cytosine-phosphate-guanine (CpG) dinucleotides proximal to the NOS2 transcription start site. Further analysis of chromatin accessibility and histone modifications demonstrated a closed conformation at the human NOS2 locus and an open conformation at the murine NOS2 locus. In examining the potential for CpG demethylation at the NOS2 locus, we found that the human NOS2 gene was resistant to the effects of demethylation agents both in vitro and in vivo. Our data demonstrate that epigenetic modifications in human macrophages are associated with CpG methylation, chromatin compaction, and histone modifications that effectively silence the NOS2 gene. Taken together, our findings suggest there are significant and underappreciated differences in how murine and human macrophages respond to inflammatory stimuli.
Details
- Title: Subtitle
- Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses
- Creators
- Thomas J Gross - Department of Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Karol KremensLinda S PowersBrandi BrinkTina KnutsonFrederick E DomannRobert A PhilibertMohammed M MilhemMartha M Monick
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.192(5), pp.2326-2338
- DOI
- 10.4049/jimmunol.1301758
- PMID
- 24477906
- PMCID
- PMC3943971
- NLM abbreviation
- J Immunol
- ISSN
- 0022-1767
- eISSN
- 1550-6606
- Publisher
- United States
- Grant note
- P30 ES005605 / NIEHS NIH HHS NIH RO1 HL096625 / NHLBI NIH HHS NIH R01 HL079901 / NHLBI NIH HHS UL1RR024979 / NCRR NIH HHS R21 HL109589 / NHLBI NIH HHS R21HL109589 / NHLBI NIH HHS R01 HL079901 / NHLBI NIH HHS NIEHS/NIH P30 ES005605 / NIEHS NIH HHS R01 HL096625 / NHLBI NIH HHS UL1 RR024979 / NCRR NIH HHS P30 CA086862 / NCI NIH HHS
- Language
- English
- Date published
- 03/01/2014
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Pulmonary, Critical Care, and Occupational Medicine; Psychiatry; Hematology, Oncology, and Blood & Marrow Transplantation; Pathology; Iowa Neuroscience Institute; Surgery; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984047743302771
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