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NOD1 recognizes the diaminopimelic acid (DAP)-containing peptide moiety of bacterial peptidoglycans (PGNs) intracellularly, and a minimum NOD1 ligand has been reported to be γ- D -glutamyl-meso-DAP (iE-DAP). In this study, we demonstrated that chemically synthesized meso-DAP and meso-lanthionine by themselves activated various human epithelial cells through NOD1 to generate anti-bacterial factors and cytokines in specified cases. In human monocytic cells, in the presence of Lipofectamine or cytochalasin D, meso-DAP induced production of cytokines. Our findings suggest that meso-DAP is a sufficient structure to activate NOD1 when incorporated intracellularly.

Interleukin (IL)-18 is one of the inflammatory cytokine which is expressed not only in activated macrophages but also in non-immune cells, such as keratinocytes and epithelial cells. It is unclear which type of cell is the major source of serum IL-18. We showed that serum levels of IL-18 were increased in mice treated with Propionibacterium acnes and lipopolysaccharide (LPS), whereas, administration of clodronate-liposomes (Clo-lip) to induce depletion of macrophages showed no obvious effect on IL-18 levels. IL-18 levels were marginal in the liver, lung and spleen. Treatment with P. acnes alone induced IL-18 in each organ, and P. acnes and LPS induced increase in IL-18 levels in the liver and spleen, but decrease in the intestines. The administration of Clo-lip in mice showed only a marginal effect on the IL-18 levels in the organs. These results suggest that IL-18 expressed in keratinocytes/epithelial cells contributes to serum IL-18 levels.

In this study, we investigated the effects of DNA methyltransferases inhibitor zebularine (ZEB) and histone deacetylases inhibitor suberoylanilide hydroxamic acid (SAHA) on the apoptosis induced by cisplatin (CDDP) or 5-fluorouracil (5-FU) in human oral squamous cell carcinoma (HSC)-3 cells. HSC-3 cells were incubated with CDDP (5 µ/ml) or 5-FU (250 µ/ml) with or without ZEB (120 µM) and/or SAHA (1.5 µM). CDDP or 5-FU alone induced apoptosis in about 30% of cells. The combination of CDDP/SAHA or CDDP/ZEB led to a significant increase in apoptotic cells up to 80% after 48 h incubation, and the triple combination of CDDP/SAHA/ZEB showed a synergetic effect on apoptosis induction. Although the combination of 5-FU/SAHA showed a moderate increase in apoptosis after 72 h, the combination of 5-FU/ZEB inhibited apoptosis rather than that of 5-FU alone. These results indicate that epigenetic active agents (ZEB and SAHA) could sensitize HSC-3 cells to apoptosis induced by these anti-cancer drugs, which may be an important characteristic of solid cancer treatment.

As histamine is an important mediator in immune responses, histamine, inflammatory cytokines, and bacterial components released in inflamed periodontal tissues may be synergistically involved in inflammatory processes. The present study showed that human gingival fibroblasts (HGF) express histamine receptors (Rs) H1R and H2R, and responded to histamine to produce interleukin (IL)-8. The stimulation of HGF with tumor necrosis factor-α, IL-1α and lipopolysaccharide markedly induced IL-8 production, and the IL-8 production was synergistically augmented in the presence of or pretreatment with histamine. The histamine response and the synergistic effect were reproduced by an H1R agonist. Selective inhibitors of mitogen-activated protein kinases (MAPKs), nuclear factor (NF)-κB, and phospholipase C (PLC) significantly inhibited the synergistic effect. These results indicate that HGF are capable of secreting IL-8 in response to histamine through H1R, and that histamine synergistically augments the inflammatory stimuli by the amplification of the MAPK and NF-κB pathway through H1R-linked PLC.

Human cationic antibacterial protein CAP18/LL-37 exhibits bactericidal and various immunobiological activities. The constitutive expression of CAP18/LL-37 in oral epithelial cells was demonstrated, and that CAP18/LL-37 activated human gingival fibroblasts to enhance production of hepatocyte growth factor, which has been shown to exert multiple biological activities. These findings might be related to restoration and regeneration of periodontal tissues.

Abiotrophia defectiva , one of the oral streptococci, possessed a relatively higher adhesive ability to the cultured human umbilical vein endothelial cells (HUVEC) as well as fibronectin and vitronectin than other oral streptococci tested. Further, A. defectiva induced HUVEC to produce IL-8 and TNF-α, and subsequently to express E-selectin, ICAM-1 and VCAM-1. Thus, A. defectiva entering into blood streams could adhere to endothelial cells and induce proinflammatory responses through cytokine productions and leukocyte adhesion molecule expressions.

Interleukin (IL)-18, an immunoregulatory and proinflammatory cytokine, has been shown to play an important pathogenic role in inflammatory and autoimmune disorders. In the present study, immunohistochemical examination showed that the expression of IL-18 was detected in acinar and ductal epithelial cells in the salivary glands of patients with Sjögren’s syndrome (SS) but not in those of healthy subjects. Human salivary gland human parotid gland cell lines (HSY) cells constitutively expressed mRNA of IL-18 and caspase-1. Receptors for IL-18 and IL-17 were expressed on the cell surface. IL-18 induced the secretion of IL-6 and IL-8 in the presence of low amount of IL-17, a T cell-derived proinflammatory cytokine. These results suggest that IL-18 expressed in salivary gland cells is associated with pathogenesis of SS in microenvironment of salivary glands in synergy with IL-17.

Sjögren’s syndrome (SS) is a chronic autoimmune disease of the exocrine glands with infiltration of lymphocytes and destruction of glandular cells. We previously reported that interleukin (IL)-18, an inflammatory cytokine that is involved in autoimmune diseases, is produced in salivary gland (SG) of SS patients. In this study, histological changes and lymphocytes subpopulations in SG of keratin 5 (K5)/IL-18 transgenic (Tg) mice overexpressing mature IL-18 using human K5 promoter were examined. Histological analysis revealed severe infiltration of lymphocytes and atrophy of glandular duct cells in SG. Flow cytometric analyses showed that T, B, NK cells and Macrophages are infiltrated in SG of the mice. These results indicated that overexpression of IL-18 with K5 promoter induced SS-like feature.

This study aimed to determine the activities of gelatinase in whole saliva before and after a meal. Paraffin-stimulated whole saliva was collected from seven healthy volunteers (male, age: 27.3 ± 1.3) at 30 min before a meal and 30 min after a meal. Gelatinase activity and collagenase activity were measured by the Gelatinase assay kit and the Collagenase assay kit, respectively. Furthermore, the saliva samples were incubated at 37°C for 2 h and the activities were measured again. All the saliva samples before a meal had gelatinase (1.07 ± 0.28 U/ml) and collagenase (0.11 ± 0.14 U/ml) activities. The gelatinase activity decreased to 10 ± 13% after a meal ( P < 0.05). At 30 min after a meal, the activity increased again and reached 56 ± 46% of the activity before a meal. The present study confirmed that whole saliva contains gelatinase and collagenase activities. The gelatinase activity in the saliva samples, especially samples obtained after a meal, increased during a 2-h incubation. It was suggested that whole saliva has an activating system for gelatinase, which may activate a latent type of gelatinase in saliva.

DNA microarray analysis clarified that lipopolysaccharide stimulation caused THP-1 cells to exclusively up-regulate inflammation- and immunity-related genes, in which several genes in the route of the Toll-like receptor signaling pathway were up-regulated.