Continuing Effect of Cytokines and Toll-Like Receptor Agonists on Indoleamine-2,3-Dioxygenase-1 in Human Periodontal Ligament Stem/Stromal Cells

Abstract

Transplanted mesenchymal stem/stromal cells (MSCs) are a promising and innovative approach in regenerative medicine. Their regenerative potential is partly based upon their immunomodulatory activities. One of the most investigated immunomediators in MSCs, such as in periodontal ligament-derived MSCs (hPDLSCs), is indoleamine-2,3-dioxygenase-1 (IDO-1) which is upregulated by inflammatory stimuli, like cytokines. However, there are no data concerning continuing IDO-1 expression in hPDLSCs after the removal of inflammatory stimuli, such as cytokines and toll-like receptor (TLR) agonist-2 and TLR-3. Hence, primary hPDLSCs were stimulated with interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, TLR-2 agonist Pam3CSK4 or TLR-3 agonist Poly I/C. IDO-1 gene and protein expression and its enzymatic activity were measured up to five days after removing any stimuli. IL-1β- and TNF-α-induced IDO-1 expression and enzymatic activity decreased in a time-dependent manner after cessation of stimulation. IFN-γ caused a long-lasting effect on IDO-1 up to five days after removing IFN-γ. Both, TLR-2 and TLR-3 agonists induced a significant increase in IDO-1 gene expression, but only TLR-3 agonist induced significantly higher IDO-1 protein expression and enzymatic activity in conditioned media (CM). IDO-1 activity of Poly I/C- and Pam3CSK4-treated hPDLSCs was higher at one day after removal of stimuli than immediately after stimulation and declined to basal levels after five days. Among all tested stimuli, only IFN-γ was able to induce long-lasting IDO-1 expression and activity in hPDLSCs. The high plasticity of IDO-1 expression and its enzymatic activity in hPDLSCs due to the variable cytokine and virulence factor milieu and the temporal-dependent responsiveness of hPDLSCs may cause a highly dynamic potential of hPDLSCs to modulate immune responses in periodontal tissues.

The Th17/Treg cell balance: crosstalk among the immune system, bone and microbes in periodontitis

“…To inhibit the immune‐inflammatory response of Th17s, proinflammatory cytokines and TLRs stimulate DCs, gingival fibroblasts, periodontal ligament stem cells etc. to express an immunosuppressive enzyme called indoleamine 2,3‐dioxygenase (IDO) 94‐96 . IDO can directly inhibit the maturation of DCs mediated by bacterial antigens or inhibit the proliferation of antigen‐specific CD4 + T cells, which is beneficial for achieving immune tolerance or reducing inflammation 97 .…”

Toll-Like Receptors and Dental Mesenchymal Stromal Cells

“…The majority of existing reports suggest that TLR ligands enhance IDO-1 gene expression in dental MSCs. The enhanced IDO-1 gene expression was induced in hPDLs by E. coli LPS [ 146 ]; in hPDLSCs by Pam3CSK4 and Poly I:C [ 147 , 148 ]; in hDPSCs by E. coli LPS [ 149 ]; in hGFs by P. gingivalis LPS, E. coli LPS, and flagellin [ 40 , 136 ]; and in hGMSCs by Poly I:C [ 150 ]. No stimulatory effect on IDO-1 gene expression was observed in hPDLSCs upon E. coli LPS stimulation [ 147 ] and in hGMSCs upon stimulation with TLR-1, 2, 4, 6, and 7 ligands [ 150 ].…”

“…In contrast, IDO-1 protein expression was enhanced in hPDLSCs by Poly I:C and in hDPSCs by E. coli LPS [ 149 ]. The enzymatic activity of IDO-1 in conditioned media was reported to be increased by Pam3CSK4 and Poly I:C in hPDLSCs [ 148 ] and by E. coli LPS in hPDLs [ 146 ]. In contrast, no effect of P. gingivalis LPS on IDO-1 activity was observed in GFs [ 40 ].…”

A Review of Antimicrobial Activity of Dental Mesenchymal Stromal Cells: Is There Any Potential?

“…The expression of IDO in resting dental MSCs is low and is stimulated by various inflammatory cytokines such as TNFα, IL-1β, and interferon (IFN)-γ, and to a lesser extent by TLR agonists, mainly by TLR3 activation [14,16,54]. The highest IDO expression and activity in dental MSCs is achieved upon the stimulation with IFN-γ [55,56]. However, the exact role of MSCderived IDO in bacterial defense has to be further investigated.…”