Interleukin-17 (IL-17) is a proinflammatory cytokine secreted by the newly described CD4؉ Th17 subset, which is distinct from classic Th1 and Th2 lineages. IL-17 contributes to bone destruction in rheumatoid arthritis but is essential in host defense against pathogens that are susceptible to neutrophils. Periodontal disease (PD) is a chronic inflammatory condition initiated by anaerobic oral pathogens such as Porphyromonas gingivalis, and it is characterized by host-mediated alveolar bone destruction due primarily to the immune response KO female mice were much more susceptible to PD bone loss than males. Moreover, female BALB/c-IL-17RA KO mice were defective in producing anti-P. gingivalis immunoglobulin G and the chemokines KC/Gro␣ and MIP-2. In contrast, male mice produced normal levels of chemokines and anti-P. gingivalis antibodies, but they were defective in granulocyte colony-stimulating factor upregulation. This study demonstrates a gender-dependent effect of IL-17 signaling and indicates that gender differences should be taken into account in the preclinical and clinical safety testing of anti-IL-17 biologic therapies.

PurposeSclerostin, an inhibitor of Wnt/β-catenin signaling, exerts negative effects on bone formation and contributes to periodontitis-induced alveolar bone loss. Recent studies have demonstrated that serum sclerostin levels are increased in diabetic patients and that sclerostin expression in alveolar bone is enhanced in a diabetic periodontitis model. However, the molecular mechanism of how sclerostin expression is enhanced in diabetic patients remains elusive. Therefore, in this study, the effect of hyperglycemia on the expression of sclerostin in osteoblast lineage cells was examined.MethodsC2C12 and MLO-Y4 cells were used in this study. In order to examine the effect of hyperglycemia, the glucose concentration in the culture medium was adjusted to a range of levels between 40 and 100 mM. Gene expression levels were examined by quantitative reverse transcription-polymerase chain reaction and Western blot assays. Top-Flash reporter was used to examine the transcriptional activity of the β-catenin/lymphoid enhanced factor/T-cell factor complex. Tumor necrosis factor-alpha (TNFα) protein levels were examined with the enzyme-linked immunosorbent assay. The effect of reactive oxygen species on sclerostin expression was examined by treating cells with 1 mM H2O2 or 20 mM N-acetylcysteine.ResultsThe high glucose treatment increased the mRNA and protein levels of sclerostin. High glucose suppressed Wnt3a-induced Top-Flash reporter activity and the expression levels of osteoblast marker genes. High glucose increased reactive oxygen species production and TNFα expression levels. Treatment of cells with H2O2 also enhanced the expression levels of TNFα and sclerostin. In addition, N-acetylcysteine treatment or knockdown of TNFα attenuated high glucose-induced sclerostin expression.ConclusionsThese results suggest that hyperglycemia increases sclerostin expression via the enhanced production of reactive oxygen species and TNFα.Graphical Abstract

Pathogen evolution and subsequent phenotypic heterogeneity during chronic infection are proposed to enhance Staphylococcus aureus survival during human infection. We tested this theory by genetically and phenotypically characterizing strains with mutations constructed in the mismatch repair (MMR) and oxidized guanine (GO) system, termed mutators, which exhibit increased spontaneous-mutation frequencies. Analysis of these mutators revealed not only strain-dependent increases in the spontaneous-mutation frequency but also shifts in mutational type and hot spots consistent with loss of GO or MMR functions. Although the GO and MMR systems are relied upon in some bacterial species to prevent reactive oxygen species-induced DNA damage, no deficit in hydrogen peroxide sensitivity was found when either of these DNA repair pathways was lost in S. aureus. To gain insight into the contribution of increased mutation supply to S. aureus pathoadaptation, we measured the rate of ␣-hemolysin and staphyloxanthin inactivation during serial passage. Detection of increased rates of ␣-hemolysin and staphyloxanthin inactivation in GO and MMR mutants suggests that these strains are capable of modifying virulence phenotypes implicated in mediating infection. Accelerated derivation of altered virulence phenotypes, combined with the absence of increased ROS sensitivity, highlights the potential of mutators to drive pathoadaptation in the host and serve as catalysts for persistent infections.

f Enterococcus faecalis is a member of the intestinal and oral microbiota that may affect the etiology of colorectal and oral cancers. The mechanisms by which E. faecalis may contribute to the initiation and progression of these cancers remain uncertain. Epidermal growth factor receptor (EGFR) signaling is postulated to play a crucial role in oral carcinogenesis. A link between E. faecalis and EGFR signaling in oral cancer has not been elucidated. The present study aimed to evaluate the association between E. faecalis and oral cancer and to determine the underlying mechanisms that link E. faecalis to EGFR signaling. We report the high frequency of E. faecalis infection in oral tumors and the clinical association with EGFR activation. Using human oral cancer cells, we support the clinical findings and demonstrate that E. faecalis can induce EGFR activation and cell proliferation. E. faecalis activates EGFR through production of H 2 O 2 , a signaling molecule that activates several signaling pathways. Inhibitors of H 2 O 2 (catalase) and EGFR (gefitinib) significantly blocked E. faecalis-induced EGFR activation and cell proliferation. Therefore, E. faecalis infection of oral tumor tissues suggests a possible association between E. faecalis infection and oral carcinogenesis. Interaction of E. faecalis with host cells and production of H 2 O 2 increase EGFR activation, thereby contributing to cell proliferation.