ABSTRACT
Periodontitis is a chronic inflammatory disease characterized by a host inflammatory response against bacteria that leads to destruction of the supporting structures of the teeth. Bacterial components of pathogens in the periodontal pocket are recognized by toll-like receptors (TLRs) that trigger an inflammatory response. In this study, we investigated the effects of the pro-inflammatory cytokine tumor necrosis factor α (TNFα) on TLR2 expression in human gingival fibroblasts. In addition, we examined the signaling pathways involved in the regulation of TNFα-induced TLR2 expression. Our results showed that TNFα increased TLR2 mRNA and protein expression. Microarray analysis and the inhibition of specific signaling pathways demonstrated that c-Jun N-terminal kinases (JNK) and nuclear factor kappa B (NF-κB) were involved in the regulation of TNFα-induced TLR2 expression in gingival fibroblasts. Furthermore, the prostaglandin E(2) (PGE(2)) regulatory enzyme cytosolic phospholipase A(2) (cPLA(2)) and the anti-inflammatory prostaglandin 15-deoxy-Δ(12,14)-prostaglandin J(2) (15d-PGJ(2)), were found to regulate TLR2 mRNA expression stimulated by TNFα. Our findings suggest that these pathways and mediators, through the regulation of TLR2 expression in gingival fibroblasts, may be involved in the pathogenesis of periodontitis. The study provides new insights into the molecular mechanisms underlying the regulation of TLR2, implicated in the chronic inflammatory disease periodontitis.
Subject(s)
Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression Regulation/drug effects , Gingiva/cytology , Signal Transduction/drug effects , Toll-Like Receptor 2/genetics , Tumor Necrosis Factor-alpha/pharmacology , Child , Child, Preschool , Fibroblasts/enzymology , Gene Expression Profiling , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Janus Kinase 2/metabolism , NF-kappa B/metabolism , Prostaglandins/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , STAT1 Transcription Factor/metabolism , Signal Transduction/genetics , Time Factors , Toll-Like Receptor 2/metabolismABSTRACT
The roles of T cells and B cells in kainic acid (KA)-induced hippocampal lesions were studied in C57BL/6 mice lacking specific T cell populations (CD4, CD8, and CD4/CD8 cells) and B cells [Igh-6(-/-)]. At 48 mg/kg of KA administrated intranasally, KA-induced convulsions were seen in all groups. However, CD4/CD8(-/-) mice exhibited the mildest seizures; the responses of CD8(-/-), Igh-6(-/-) and wild-type mice were intermediate, whereas CD4(-/-) mice displayed much more severe clinical signs and 100% early mortality, indicating that a deficiency of CD4 T cells obviously increased susceptibility to KA-induced brain damage. Histopathological analysis of the mice that survived 7 days after KA administration revealed that CD4/CD8(-/-) mice had the fewest pathologic changes but Igh-6(-/-) mice showed more severe lesions in area CA3 of the hippocampus than CD8(-/-) and wild-type mice. Reactive astrogliosis were prominent in all KA-treated mice. Locomotor activity as assessed by open-field test increased after KA administration in Igh-6(-/-) and wild-type mice only. These results denote the influence of the adaptive immune response on KA-induced hippocampal neurodegeneration and suggest that B cell and T cell subsets may contribute differently to the pathogenesis.
