MAPKs, activator protein‐1 and nuclear factor‐κB mediate production of interleukin‐1β‐stimulated cytokines, prostaglandin E2 and MMP‐1 in human periodontal ligament cells

Murayama R, Kobayashi M, Takeshita A, Yasui T, Yamamoto M. MAPKs, activator protein-1 and nuclear factor-κB mediate production of interleukin-1β-stimulated cytokines, prostaglandin E2and MMP-1 in human periodontal ligament cells. J Periodont Res 2011; 46: 568–575. © 2011 John Wiley & Sons A/S Background and Objective:  Determination of the interleukin-1 (IL-1) signaling cascades that lead to the production of various inflammatory mediators and catabolic factors may clarify attractive targets for therapeutic intervention for periodontitis. We comprehensively assessed the involvement of MAPKs, activator protein-1 (AP-1) and nuclear factor-κB (NF-κB) in IL-1β-induced production of interleukin-6 (IL-6), interleukin-8 (IL-8), prostaglandin E2 (PGE2) and MMP-1 in human periodontal ligament cells. Material and Methods:  Human periodontal ligament cells were pretreated with an inhibitor for each of the MAPKs or NF-κB and subsequently treated with IL-1β. Following treatment, phosphorylation of three types of MAPK (ERK, p38 MAPK and c-Jun N-terminal kinase), IκB kinase (IKK) α/β/γ and IκB-α, as well as the DNA binding activity of AP-1 and NF-κB and the production of IL-6, IL-8, PGE2 and MMP-1, were determined by western blotting, a gel mobility shift assay and ELISA, respectively. Results:  The three MAPKs, simultaneously activated by IL-1β, mediated the subsequent DNA binding of AP-1 at various magnitudes, while IKKα/β/γ, IκB-α and NF-κB were also involved in the IL-1 signaling cascade. Furthermore, IL-1β stimulated the production of IL-6, IL-8, PGE2 and MMP-1 via activation of the three MAPKs and NF-κB, because inhibitors of these significantly suppressed the IL-1β-stimulated production of these factors. Conclusion:  Our results strongly suggest that MAPK, AP-1 and NF-κB mediate the IL-1β-stimulated synthesis of IL-6, IL-8, PGE2 and MMP-1 in human periodontal ligament cells. Therefore, inhibition of activation of MAPK, AP-1 and/or NF-κB may lead to therapeutic effects on progression of periodontitis.