Inducing phospholipase A2 and cyclooxygenase-2 expression and prostaglandins' production of human dental pulp cells by activation of NOD receptor and its downstream signaling

Dental caries with invasion and infection by microorganisms may induce pulpitis and intolerable pain. L-Ala-γ-D-Glu-mDAP (TriDAP) is a DAP-comprising muramyl tripeptide and a peptidoglycan degradation product found in gram-negative pulpal pathogens. TriDAP activates nucleotide-binding oligomerization domain1/2 (NOD1/NOD2) and induces tissue inflammatory responses. This study aimed to test whether TriDAP stimulates cytosolic phospholipase A2 (cPLA2), cyclooxygenase-2 (COX-2), and prostanoid production in human dental pulp cells (HDPCs) and their inhibition by signal transduction inhibitors, melatonin, and eugenol. We found that TriDAP stimulated cPLA2 and COX-2 expression as well as prostaglandin E₂ (PGE₂) and PGF_2α secretion in HDPCs. TriDAP activated TAK1, MEK/ERK, and p38 signaling. COX-2 expression, PGE₂, and PGF_2α production induced by TriDAP were prevented by 5Z-7oxozeaenol, SB203580, and U0126. Moreover ASB14780 (a cPLA2 inhibitor) and the clinical drugs melatonin and eugenol suppressed TriDAP- and Poly(I:C)-stimulated PGE₂ and PGF_2α production. These results indicate that NOD activation in HDPCs may stimulate COX-2 expression and prostaglandin production, which are crucial in pulpal inflammatory and repair responses. The effects of TriDAP and Poly(I:C) were associated with TAK1, p38, MEK/ERK, and cPLA2 in pulpal inflammation. PLA2 inhibitors, melatonin, and eugenol can be used to control pulpal inflammation associated with NOD1/2 and TLR3 activation.