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'-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.

Smooth muscle-specific Gsα deletion exaggerates angiotensin II-induced abdominal aortic aneurysm formation in mice in vivo

“…Previous study showed that HuR could increase the stability of MMP2 and MMP9 mRNAs [35]. Moreover, some inflammatory cytokines such as CCL-2 and IL-6 are the targets of HuR [36,37]. Thus, HuR may participate in the AAA progression through regulating some different pathways.…”

“…However, the possible mechanisms were still unclear. Previous studies show that HuR regulates the expression of many inflammatory cytokines including IL-6, ICAM-1, CCL-2, IL-17C and TNF-α through binding to their mRNAs [36][37][38][39]. Thus, the increased inflammation caused by Gsα deficiency may be resulted from increased HuR expression.…”

Interleukin‐4‒induced posttranscriptional gene regulation of CCL26 by the RNA‐binding protein HuR in primary human nasal polyp‒derived epithelial cells

“…Stabilization or decay of ARE‐containing mRNAs through interaction with RNA‐binding proteins has been recognized as an important mechanism of posttranscriptional regulation for inflammatory cytokine genes . HuR, a ubiquitously expressed RNA‐binding protein, is linked to the progression of various chronic inflammatory diseases, such as rheumatoid arthritis, diabetes mellitus, and some inflammatory diseases . It has been shown in vitro that HuR binds to and interacts with AREs in mRNAs producing several inflammatory mediators such as cyclooxygenase‐2 (COX‐2), IL‐6, tumor necrosis factor‐alpha (TNF‐α), and chemokine receptor 6 (CCR6) .…”

Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

“…The 3′UTR is important for the post-transcriptional regulation of genes. Many RBPs, including human antigen R (HuR) [30], tristetraprolin (TTP) [31], and MCPIP1, have been reported to regulate mRNA stability by the 3'UTR.…”