Proinflammatory effects of muramyldipeptide on human gingival fibroblasts.

Hosokawa I, Hosokawa Y, Ozaki K, Yumoto H, Nakae H, Matsuo T. Proinflammatory effects of muramyldipeptide on human gingival fibroblasts. J Periodont Res 2010; 45: 193–199. © 2010 The Authors. Journal compilation © 2010 Blackwell Munksgaard Background and Objective: Because human gingival fibroblasts (HGFs) are the predominant cells in periodontal tissues, we hypothesized that HGFs are contributed to receptors for components of bacteria. In this study, we focused on expression and function of nucleotide binding oligomerization domain 2 (NOD2) in HGFs, which is a mammalian cytosolic pathogen recognition molecule. Material and Methods: Expression of NOD2 in HGFs was examined by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry. Production of interleukin (IL)-6, IL-8, cc chemokine ligand2, cxc chemokine ligand10 (CXCL10) and CXCL11 from HGFs was examined by enzyme-linked immunosorbent assay (ELISA). We used RT-PCR and immunohistochemistry to detect the NOD2 expression in human gingival tissues. Results: We found clear NOD2 expression in HGFs. Upon stimulation with NOD2 agonist, muramyldipeptide (MDP), production of proinflammatory cytokines was enhanced. Moreover, MDP-induced production of proinflammatory cytokines was inhibited in a different manner by mitogen-activated protein kinase inhibitors and phosphatidylinositol 3-kinase inhibitor. Furthermore, MDP enhanced CXCL10 and CXCL11 productions by tumor necrosis factor-α (TNF-α)- or interferon-γ (IFN-γ)-stimulated HGFs, although MDP alone did not induce these chemokines. TNF-α and IFN-γ increased NOD2 expression in HGFs. In addition, we detected NOD2 expression in mononuclear cells and HGFs in periodontally diseased tissues. Conclusion: These findings indicate that MDP which induces production of cytokines and chemokines from HGFs is related to the pathogenesis of periodontal disease. [ABSTRACT FROM AUTHOR]