CC chemokine ligand 17 in periodontal diseases: expression in diseased tissues and production by human gingival fibroblasts

Abstract

Background and objective: It has been reported that T helper 2 (Th2) cells are related to exacerbation of periodontal disease. However, it is uncertain how the migration of Th2 cells is controlled. In this study, we examined the expression of CC chemokine ligand 17 (CCL17), which is a Th2 chemokine, in periodontal tissues. Moreover, we investigated the effects of cytokines and toll-like receptor (TLR) ligands on the production of CCL17 by human gingival fibroblasts (HGFs).

Material and methods: We used immunohistochemistry and reverse transcriptase-polymerase chain reaction (RT-PCR) to detect CCL17 in periodontal tissues. HGFs were exposed to cytokines and TLR ligands. Expression of CCL17 was examined by RT-PCR and enzyme-linked immunosorbent assay. We used signal transduction inhibitors in some experiments.

Results: Both CCL17 and its receptor, CC chemokine receptor 4 (CCR4), were expressed in diseased periodontal tissues. A combination of tumour necrosis factor alpha (TNF-alpha) and interleukin (IL)-4/IL-13 increased CCL17 expression. Moreover, treatment of HGFs with a low dose of interferon-gamma (IFN-gamma) in combination with TNF-alpha and IL-4 or IL-13 had synergistic effects on the production of CCL17, whereas a high dose of IFN-gamma inhibited CCL17 production. Furthermore, Escherichia coli (E. coli) lipopolysaccharide (TLR4 ligand) and Pam3CSK4 (TLR2 ligand) inhibited CCL17 production by TNF-alpha + IL-4-stimulated HGFs, while CpG DNA (TLR9 ligand) enhanced TNF-alpha + IL-4 induced-CCL17 production by HGFs. Furthermore, a c-Jun NH2 terminal kinase (JNK) inhibitor, a phosphatidylinositol-3-kinase (PI3K) inhibitor and a nuclear factor kappa B (NF-kappa B) inhibitor inhibited CCL17 production by HGFs.

Conclusion: These results suggest that the CCL17 produced by HGFs may be involved in the migration of Th2 cells into inflamed tissues, and provide evidence that CCL17 production is controlled by cytokines and TLR ligands in periodontal disease.