Signaling Pathways Regulating IL-1α-induced COX-2 Expression

Interleukin-1α(IL-1α) stimulates the production of prostaglandin E2 (PGE2) in odontogenic keratocyst fibroblasts. However, the signaling pathways remain obscure. In this study, we investigated IL-1αsignaling pathways that regulate cyclooxygenase-2 (COX-2) expression in odontogenic keratocyst fibroblasts. IL-1αincreased the expression of COX-2 mRNA and protein, and PGE2 secretion in the fibroblasts. IL-1αincreased the phosphorylation of extracellular signal-regulated protein kinase-1/2 (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK). PD-98059, SB-203580, SP-600125, and PDTC—which are inhibitors of ERK1/2, p38, JNK, and nuclear factor-κB (NF-κB), respectively—attenuated the IL-1α-induced COX-2 mRNA expression and activated protein kinase C PGE2 secretion. IL-1α(PKC), and PKC inhibitor staurosporine inhibited IL-1α-induced phosphorylation of ERK1/2, p38, and JNK, and decreased IL-1α-induced COX-2 mRNA expression. Thus, in odontogenic keratocyst fibroblasts, IL-1αmay stimulate COX-2 expression both through the PKC-dependent activation of ERK1/2, p38, and JNK signaling pathways, and through the NF-κB cascade.