Interleukin‐1‐induced cyclooxygenase‐2 and inducible nitric oxide synthase expression in human OA chondrocytes is associated with histone H3K4 methylation

Abstract

ObjectiveIn the present study, we investigated the role of H3K4 methylation in interleukin‐1β (IL‐1)‐induced COX‐2 and iNOS expression in human OA chondrocytes.MethodsChondrocytes were stimulated with IL‐1 for various time periods and the expression of iNOS and COX‐2 mRNAs and proteins were evaluated using RT‐PCR and Western blotting, respectively. H3K4 methylation at the iNOS and COX‐2 promoters was evaluated using ChIP assays. The role of histone methylation was further evaluated using the methyltransferase inhibitor, 5′‐deoxy‐5′(methylthio) adenosine (MTA).ResultsIL‐1 induced iNOS and COX‐2 mRNA and protein in a dose‐ and time‐dependent manner. The induction of iNOS and COX‐2 expression by IL‐1 was associated with H3K4 di‐ and trimethylation at the iNOS and COX‐2 promoters, whereas the levels of H3K4 monomethylation remained unchanged. Treatment with MTA inhibited IL‐1‐induced H3K4 methylation as well as IL‐1‐induced iNOS and COX‐2 expression.ConclusionThese results indicate that H3K4 methylation contributes to IL‐1‐induced iNOS and COX‐2 expression and suggest that this pathway could be a potential target for pharmacological intervention in the treatment of OA disease.