These findings indicate that LL-37 induces IL-8 expression via the P2X(7) receptor and the MEK1/2-dependent p44/42 MAP kinases in HGFs, suggesting both direct and indirect involvement of LL-37 in neutrophil recruitment into an inflammatory site within diseased periodontal tissues.

Head and neck cancer, including oral cancer, is the sixth most common cancer in humans worldwide. More than 90% of oral cancers are of squamous cell carcinoma type. Recent studies have shown a strong relationship between human papillomavirus (HPV) infection and head and neck cancer, especially oropharyngeal squamous cell carcinoma (OPSCC) and oral squamous cell carcinoma (OSCC). Moreover, the incidence of HPV-related OSCC appears to be on the rise while HPV-unrelated OSCC tends to have stabilized in the past decades. p16, a tumor suppressor gene, normally functions as a regulator of the cell cycle. Upon infection with high-risk types of HPV (HR-HPV), particularly types 16,

Periodontal disease is caused by microorganisms and host-derived inflammation involving increased cyclooxygenase-2 (COX-2) expression and prostaglandin E₂ (PGE₂) production. We previously demonstrated that human β-defensin-3 induces COX-2 and PGE₂ in human gingival fibroblasts (HGFs). We, therefore, aimed to examine the inducible effects of LL-37, the only cathelicidin expressed in humans, on COX-2 expression and PGE₂ synthesis in HGFs and to elucidate the relevant signaling pathways. The COX-2 expression was upregulated by LL-37 in dose- and time-dependent manners. Accordingly, the synthesis of PGE₂ in cell-free culture supernatants was raised by LL-37 (p < 0.01) and blocked by NS-398, a specific COX-2 inhibitor (p < 0.01). P2X inhibitors and a neutralizing antibody against P2X₇ purinergic receptor significantly abrogated COX-2 induction and PGE₂ production by LL-37 (p < 0.01). LL-37 upregulated COX-2 expression and PGE₂ synthesis via activation of extracellular signal-regulated kinase (ERK) and p46 c-Jun N-terminal kinase (JNK), while interleukin-1β did so via nuclear factor-ĸB and all three mitogen-activated protein kinases. In summary, LL-37 can control arachidonic acid metabolism by induction of COX-2 expression and PGE₂ synthesis via the P2X₇ receptor, ERK, and p46 JNK. The pro-inflammatory effects of LL-37 may be essential for initiating oral mucosal inflammation in periodontal disease.

These findings indicate that epithelial human beta-defensin-3 functions as a proinflammatory mediator in controlling arachidonic acid metabolism in underlying fibroblasts.

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Human beta-defensin expression correlates with differentiation in oral epithelium, and calcium ion, an important regulator of epithelial differentiation, plays a critical role in regulation of human beta-defensin-2 (hBD-2) mRNA expression. Phospholipase D (PLD) also regulates epithelial differentiation. Therefore, we examined the role of PLD in hBD-2 up-regulation by cell wall extract of Fusobacterium nucleatum and phorbol 12-myristate 13-acetate (PMA), two known hBD-2 activators. We found that hBD-2 mRNA up-regulation in human gingival epithelial cells (HGECs) by these two activators was mediated by PLD activation and blocked by ethanol and 1-butanol, PLD inhibitors. PLD activity was induced by stimulation with these two activators, and phosphatidic acid (PA), a product generated from the PLD enzymatic activity, was detected in stimulated HGECs. Dioctanoyl PA commonly used for PA induced hBD-2 mRNA expression. mRNAs for PLD1 alpha and beta splice variants as well as PLD1 protein were constitutively expressed, whereas mRNA and protein for PLD2 were expressed at much lower levels than those for PLD1. Moreover, pre-treatment with (+/-)-propanolol, an inhibitor of phosphatidic acid phosphohydrolases that are the downstream signaling molecules in the PLD pathway, significantly blocked hBD-2 mRNA induction by PMA in a dose-dependent manner. In conclusion, these findings indicate the involvement of PLD activation in hBD-2 up-regulation in HGECs, which correlates with the state of epithelial differentiation.

Background/purpose Although some studies have shown induction of cyclooxygenase 2 (COX-2) in oral lichen planus (OLP), an association between COX-2 upregulation and OLP clinical severity has not been investigated. Therefore, we aimed to compare COX-2 expression in OLP with that in normal oral tissues, and to determine correlations between COX-2 expression and both clinical criteria and visual analog scale (VAS) scores. Materials and methods COX-2 expression was studied in 25 OLP and 13 normal oral tissues by immunohistochemistry. Both clinical criteria and VAS scores were used to evaluate the clinical severity of OLP. The differences in COX-2 expression between OLP and normal tissues, and the correlations between COX-2 expression and clinical severity were determined by the nonparametric statistical tests. Results COX-2 expression was significantly increased in OLP epithelium when compared with normal epithelium (P < 0.001), and intense COX-2 staining in inflammatory infiltrates was observed in the OLP lamina propria. COX-2 expression in OLP epithelium and inflammatory infiltrates was significantly correlated with the clinical criteria score ( r = 0.428, P = 0.007, and r = 0.681, P < 0.001, respectively), whereas a significant correlation with the VAS score was observed only in OLP inflammatory infiltrates ( r = 0.605, P < 0.001). Conclusion Enhanced COX-2 expression in both OLP epithelium and inflammatory infiltrates correlates well with the clinical severity. An association between VAS score and COX-2 expression in OLP inflammatory infiltrates suggests an important role of additional COX-2 expression from inflammation in causing pain in OLP patients.

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