DNA methyltransferase inhibitors increase NOD-like receptor activity and expression in a monocytic cell line

Abstract

Background: The intracellular NOD-like receptor (NLR) family of pathogen recognition receptors (PRRa) is involved in initiating the innate immune response of which NOD1 and NOD2 are the best-characterized members. Aberrant expression of NOD1 and NOD2 has been uncovered in a number of chronic inflammatory diseases, such as inflammatory bowel disease and rheumatoid arthritis. However, the mechanism underlying NOD1/NOD2 gene expression regulation is still in its infancy. Epigenetic modifications such as DNA methylation and histone acetylation regulate the expression of genes and alterations in their patterns have been linked to many inflammatory diseases. This study investigated whether epigenetic modifying drugs affect the regulation of NOD1/NOD2 activity and expression. DNA methyltransferase inhibitors have recently been used in the treatment of myelodysplastic syndrome and as combination therapy in cancer but the full extent of their effects has not been quantified.

Methods: Pharmacological inhibition of epigenetic enzymes in a human monocytic THP-1 cell line was carried out and NOD1/NOD2 expression and pro-inflammatory responses were quantified.

Results: Cells primed with a DNA methyltransferase inhibitor (but not a histone deacetylase [HDAC] inhibitor) were found to be consistently more responsive to NOD1/NOD2 stimulation and had increased basal expression.

Conclusion: The novel experimentation carried out here suggests for the first time that NOD1/NOD2 receptor activity and expression in monocytes are possibly regulated directly by DNA methylation.

Keywords:

• NOD-like receptors
• inflammation
• epigenetics
• DNA methylation
• monocytes

Acknowledgments

The authors wish to acknowledge Dr. Danny Kerr for technical assistance and Dr. Aideen Ryan and Prof. Laurence Egan for useful discussion. The authors wish to acknowlede funding from the Hardiman scholarship at NUI Galway.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

CF was funded by a Hardiman Scholarship from the National University of Ireland, Galway.