IL-8 and IDO Expression by Human Gingival Fibroblasts via TLRs

Abstract

Human gingival fibroblasts (HGFs), a predominant cell type in tooth-supporting structure, are presently recognized for their active role in the innate immune response. They produce a variety of inflammatory cytokines in response to microbial components such as LPS from the key periodontal pathogen, Porphyromonas gingivalis. In this study, we demonstrated that HGFs expressed mRNA of TLRs 1, 2, 3, 4, 5, 6, and 9, but not TLRs 7, 8, and 10. Stimulation of HGFs with highly purified TLR2 ligand (P. gingivalis LPS), TLR3 ligand (poly(I:C)), TLR4 ligand (Escherichia coli LPS), and TLR5 ligand (Salmonella typhimurium flagellin) led to expression of IL-8 and IDO. A potent TLR 9 ligand, CpG oligodeoxynucleotide 2006 had no effect, although HGFs showed a detectable TLR9 mRNA expression. No significant enhancement on IL-8 or IDO expression was observed when HGFs were stimulated with various combinations of TLR ligands. Surprisingly, the TLR9 ligand CpG oligodeoxynucleotide 2006 was able to specifically inhibit poly(I:C)-induced IL-8 and IDO expression. TNF-α enhanced TLR ligand-induced IL-8 production in HGFs, whereas IFN-γ enhanced TLR ligand-induced IDO expression. HGF production of IDO in response to P. gingivalis LPS, IFN-γ, or the two in combination inhibited T cell proliferation in MLRs. The observed T cell inhibition could be reversed by addition of either 1-methyl-dl-tryptophan or l-tryptophan. Our results suggest an important role of HGFs not only in orchestrating the innate immune response, but also in dampening potentially harmful hyperactive inflammation in periodontal tissue.

Tryptophan Deprivation Induces Inhibitory Receptors ILT3 and ILT4 on Dendritic Cells Favoring the Induction of Human CD4+CD25+ Foxp3+ T Regulatory Cells

“…IDO expression is induced mainly by IFNs and LPS in cells from various organs and within tissue-invading cells during inflammation (4,15,16). IDO activity of APCs, epithelial cells, fibroblasts, or tumor cells has been demonstrated to block T cell responses toward allogeneic fetuses, grafts, and tumors, and may play a role in the prevention of allergic disease (17)(18)(19)(20)(21)(22)(23)(24). Downstream metabolites of Trp, which are produced by IDO activity in murine DCs, are able to convert otherwise immunogenic and IDO-incompetent murine DCs into tolerizing DCs (25).…”

Human gingival fibroblasts express functional chemokine receptor CXCR6

“…Recently, Mohanonda and colleagues reported that the TLR-2, TLR-3, TLR-4 and TLR-5 ligands enhanced IL-8 production from HGF, although the TLR-9 ligand did not [14]. Moreover, they reported that the TLR-9 ligand suppressed IL-8 production from TLR-3 ligand-stimulated HGF [14].…”

“…Recently, Mohanonda and colleagues reported that the TLR-2, TLR-3, TLR-4 and TLR-5 ligands enhanced IL-8 production from HGF, although the TLR-9 ligand did not [14]. Moreover, they reported that the TLR-9 ligand suppressed IL-8 production from TLR-3 ligand-stimulated HGF [14]. Their report may explain why the TLR-9 ligand It is reported that both T helper type 1 (Th1) and Th2 cells exist in periodontally diseased tissues [15].…”

The Study of Ozone Ointment on Human Gingival Fibroblasts Cell Proliferation Ability and Anti-Inflammatory

“…Furthermore, HGFs have previously been reported to express the genes for Toll-like receptors (TLR) 1-5 and 9, which are widely known as receptors for pathogens; in particular, TLR-2,3,4 and 5 have been reported to be specifically involved in the expression of IL8 24) , and TLR-2 is known to be involved in the expression of IL-6 25) . These results support the fi nding of enhanced production of these cytokines following pathogen stimulation.…”