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Roles of TLR2, TLR4, NOD2, and NOD1 in Pulp Fibroblasts

Department of Conservative Dentistry, Institute of Health Biosciences, The University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan

Correspondence: ^* yumoto{at}dent.tokushima-u.ac.jp

Pulp fibroblasts express various pro-inflammatory mediators leading to marked infiltration of inflammatory cells in the progression of pulpitis. We hypothesized that pulp fibroblasts play roles in the recognition of invaded caries-related bacteria and the subsequent innate immune responses. We found clear expressions of TLR2, NOD1, and NOD2 and a faint expression of TLR4 in human dental pulp fibroblasts (HDPF) by RT-PCR and flow cytometry. We also observed that various pro-inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostaglandin E₂ and its key enzyme COX-2, not iNOS or caspase-1, were markedly up-regulated by stimulation with these TLR and NOD agonists. More over, the NOD2 agonist acted synergistically with the TLR2, not the TLR4, agonist to stimulate the production of pro-inflammatory mediators in HDPF. These findings indicate that TLR2, TLR4, NOD2, and NOD1 in HDPF are functional receptors, and NOD2 is a modulator of signals transmitted through TLR2 in pulpal immune responses, leading to progressive pulpitis.

Key Words: TLR • NOD • dental pulp fibroblast • inflammation

Abbreviations: HDPF, human dental pulp fibroblasts • IL, interleukin • MCP-1, monocyte-chemoattractant protein-1 • IP-10, interferon--inducible protein-10 • LPS, lipopolysaccharide • ICAM-1, intercellular adhesion molecule-1 • PG, prostaglandin • iNOS, inducible nitric oxide synthase • PRR, pattern recognition receptor • PAMP, pattern-associated molecular pattern • TLR, Toll-like receptor • NOD, nucleotide-binding oligomerization domain • MDP, muramyldipeptide • NF-B, nuclear factor-B • RT-PCR, reverse-transcription polymerase chain-reaction • DMEM, Dulbecco’s modified Eagle’s medium • iE-DAP, -D-glutamyl-meso-diaminopimelic acid • iE-Lys, -D-glutamyl-lysine • MDP-LL, N-acetylmuramyl-L-alanyl-L-isoglutamine • GAPDH, glyceraldehyde-3-phosphate dehydrogenase • ELISA, enzyme-linked immunosorbent assay • VCAM-1, vascular cell adhesion molecule-1 • FITC, fluorescein isothiocyanate • COX-2, cyclooxygenase-2

Journal of Dental Research, Vol. 88, No. 8, 762-767 (2009)
DOI: 10.1177/0022034509341779


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