Besides TLR2 and TLR4, in vitro-differentiated Venetoclax molecular weight odontoblasts constitutively express TLR1, 3, 5, 6 and 9 genes [53]. A recent study has reported that TLR9 is expressed in the mouse odontoblast-like cell line MDPC-23, a spontaneously immortalized cell line derived from fetal
mouse molar dental papillae, and that CpG DNA induces potent pro-inflammatory cytokine expression via the activation of TLR9 [56]. Additionally, an immunohistochemical report revealed that the NOD2 protein expression was localized in odontoblasts and some vascular endothelial cells in normal human dental pulp 57]. However, more detailed studies on the functional role of these PRRs in the odontoblasts to recognize intradentinal irritation of caries-related bacteria are required in future. Dental pulp cells, especially dental pulp fibroblasts, are known to
produce various inflammatory mediators, LY294002 manufacturer such as IL-8, IL-6 and vascular endothelial growth factor (VEGF), in response to the components of caries-related bacteria, prior to the discovery and establishment of the innate immune system feature that PRRs including TLRs recognize various PAMPs [29], [31], [32] and [58]. TLR2, TLR3, TLR4 and TLR5 expressions have been determined in dental pulp fibroblasts and their specific agonists can induce TLR-mediated inflammatory signals [54], [55], [59] and [60], although immunohistological detection of TLRs was not clear in the fibroblasts of dental pulp tissues [49] and [52]. A recent study has shown that the dental pulp stem cells as well as the dental pulp fibroblasts express TLR4, and that LPS-induced VEGF is dependent upon mitogen-activated protein kinase (MAPK) activation [61]. In our study, flow cytometric analysis showed that the expression level of TLR2 was higher than that of TLR4 in human dental pulp fibroblasts [59]. In accordance with this analysis, the levels of pro-inflammatory mediators, such as CXCL10, IL-8 and PGE2, Phosphatidylethanolamine N-methyltransferase induced by LPS stimulation were much lower than those
induced by Pam3CSK4. On the other hand, another group has shown that CXCL10 expression in dental pulp fibroblasts was up-regulated by LPS but not LTA, a TLR2-agonist [54]. These results suggest differences of reactivity between Pam3CSK4 and LTA to elicit chemokine production. In fact, our previous report indicates that the dental pulp fibroblasts can produce CXCL10 in response to peptidoglycan, but not LTA [24]. MAPKs have been implicated in many physiologic processes, including cell proliferation, differentiation and death [62], [63] and [64]. Three major types of MAPKs in mammalian cells are extracellular signal regulated kinase (ERK) 1/2, p38 MAPK and c-Jun NH2-terminal kinases (SAP/JNK). NF-κB is an oxidation-sensitive transcription factor that plays a critical role in the regulation of various genes that are important in cellular responses, including inflammation, innate immunity, growth and cell death [65].