The induced RNA-binding protein, HuR targets 3'-UTR region of IL-6 mRNA and enhances its stabilization in periodontitis

Abstract

RNA-binding proteins (RBPs) regulate mRNA stability by binding to the 3'-UTR region of mRNA. Human antigen-R (HuR), one of the RBPs, is involved in the progression of diseases, such as rheumatoid arthritis, diabetes mellitus, some inflammatory diseases. Interleukin (IL)-6 is a major inflammatory cytokine regulated by HuR binding to mRNA. Periodontal disease (PD) is also an inflammatory disease caused by elevations in IL-6 following an infection by periodontopathognic bacteria. The involvement of HuR in the progression of PD was assessed using in vitro and in vivo experiment.

Immunohistochemistry of inflamed periodontal tissue showed the strong staining of HuR in the epithelium and connective tissue. HuR mRNA and protein level was increased following a stimulation with Porphyromonas gingivalis (Pg), one of the periodontopathogenic bacteria, LPS derived from Pg (PgLPS), and tumor necrosis factor (TNF)-α in OBA-9, an immortalized human gingival epithelial cell. The luciferase activity of 3'-UTR of IL-6 mRNA was increased by TNF-α, Pg, and PgLPS in OBA-9. Luciferase activity was also increased in HuR-overexpressing OBA-9 following a bacterial stimulation. The down-regulation of HuR by siRNA resulted in a decrease in the mRNA expression and production of IL-6. In contrast, the overexpression of HuR increased IL-6 mRNA expression and production in OBA-9. The HuR inhibitor, quercetin suppressed Pg-induced HuR mRNA expression and IL-6 production in OBA-9. An oral inoculation with quercetin also inhibited bone resorption in ligature-induced periodontitis model mice as a result of downregulation of IL-6. These results show that HuR modulates inflammatory responses by regulating IL-6. This article is protected by copyright. All rights reserved.