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.