Immunomodulation by Periodontal Ligament Cells is Defined by Inflammatory Environment

Objectives: Human periodontal ligament cells (hPDLCs) play an important role in periodontal tissue homeostasis and regeneration. The function of these cells in vivo depends largely on their immunomodulatory ability, which is enhanced by various inflammatory cytokines like interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-1β. Thus, the activity of immune cells and immunomodulatory ability of hPDLCs are regulated by complex reciprocal mechanisms. To date, the effect of different inflammatory cytokines on the immunomodulatory abilities of hPDLCs was never directly compared.
Methods: This study compared the effect of IFN-γ, TNF-α and IL-1β treated primary hPDLCs on CD4⁺ T cell proliferation and macrophage polarization status in an indirect co-culture model. Additionally, the effects of IFN-γ, TNF-α and IL-1β on the gene and protein expression levels of specific immunomodulatory factors in hPDLCs were investigated, such as indoleamine-2,3-dioxygenase-1, programmed cell death 1 ligand (PD-L) 1, PD-L2, prostaglandin E₂, and TNF-inducible gene 6 protein.
Results: Both qualitative and quantitative differences in the immunomodulation by hPDLCs were observed depending on the type of inflammatory cytokines. Proliferation of CD4⁺ T cells was inhibited by hPDLCs and this effect was enhanced by IFN-γ and IL-1β, but not by TNF-α. The effect of IFN-γ was significantly higher than that of IL-1β. The expression of pro- and anti-inflammatory proteins in macrophages was differently affected by hPDLCs primed with various cytokines. The expression of TNF-α and IL-12a by macrophages was promoted mainly by IFN-γ primed hPDLCs. CC-chemokine ligand (CCL)-2, IL-10 and transglutaminase-2 expressions were mainly induced by IL-1β primed hPDLCs. Finally, IFN-γ, TNF-α and IL-1β induced specific expression patterns of immunomediators in hPDLCs.
Conclusions: Our data show that particular inflammatory cytokines activate specific immunomodulatory mechanisms in hPDLCs and the expression of specific immunomodulatory factors. This suggests that the complex reciprocal interaction between hPDLCs and immune cells is largely determined by the local microenvironment.