The induced RNA‐binding protein, HuR, targets 3′‐UTR region of IL‐6 mRNA and enhances its stabilization in periodontitis. (8th March 2018)

• Record Type: Journal Article
• Authors: Ouhara, K.; Munenaga, S.; Kajiya, M.; Takeda, K.; Matsuda, S.; Sato, Y.; Hamamoto, Y.; Iwata, T.; Yamasaki, S.; Akutagawa, K.; Mizuno, N.; Fujita, T.; Sugiyama, E.; Kurihara, H.
• Is Part Of: Clinical and experimental immunology. Volume 192:Number 3(2018:Jun.)
• Page Start: 325
• Page End: 336
• Publication Date: 2018-03-08
• Subjects: HuR -- IL‐6 -- periodontitis -- Porphyromonas gingivalis -- RNA‐binding protein; Immunopathology -- Periodicals; 616.079
• DOI: 10.1111/cei.13110
• Languages: English
• ISSNs: 0009-9104

Abstract

Summary: RNA‐binding proteins (RBPs) regulate mRNA stability by binding to the 3′‐untranslated region (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 and 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 periodontopathogenic bacteria. The involvement of HuR in the progression of PD was assessed using in‐vitro and in‐vivo experiments. Immunohistochemistry of inflamed periodontal tissue showed strong staining of HuR in the epithelium and connective tissue. HuR mRNA and protein level was increased following stimulation with Porphyromonas gingivalis (Pg), one of the periodontopathogenic bacteria, lipopolysacchride (LPS)‐derived from Pg (PgLPS) and tumour 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‐over‐expressing OBA‐9 following a bacterial stimulation. Down‐regulation of HuR by siRNA resulted in a decrease in mRNA expression and production of IL‐6. In contrast, the over‐expression 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 down‐regulation of IL‐6. These results show that HuR modulates inflammatory responses by regulating IL‐6. Abstract : This illustration is showing the proposed mechanism of IL‐6 elevations by HuR with a Pg stimulation. Up‐regulated HuR stimulated by P. gingivalis binds to the 3'‐UTR of IL‐6 mRNA, and this binding results in an increase in the stability of IL‐6 mRNA. On the other hand, the mRNA expression of IL‐6 and HuR is not induced under normal conditions (without a stimulation).