Cytokines differently define the immunomodulation of mesenchymal stem cells isolated from the periodontal ligament

• Published in: Cytotherapy (Oxford, England) England), 2020-05, Vol.22 (5), p.S68-S69
• Main Authors: Behm, C., Blufstein, A., Gahn, J., Kubin, B., Moritz, A., Rausch-Fan, X., Andrukhov, O.
• Format: Article
• Language: English
• ISSN: 1465-3249; 1477-2566
• DOI: 10.1016/j.jcyt.2020.03.105

Periodontal ligament derived mesenchymal stem cells (hPDLSCs) fulfil the minimal criteria of the International Society for Cellular Therapy (ISCT) for mesenchymal stem/stromal cells. In periodontal tissues these cells play a crucial role in tissue homeostasis and regeneration. The in vivo function of hPDLSCs is mainly executed by their immunomodulatory properties and is reciprocally affected by inflammatory cytokines which are secreted by immune cells. Such inflammatory cytokines are interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-1β, which trigger various signaling pathways and consequently may regulate immunomodulatory activities of hPDLSCs differently. The effect of these cytokines on hPDLSCs’ immunomodulation was not directly compared, so far. Hence, we directly compared in an indirect in vitro co-culture model the effect of IFN-γ, TNF-α or IL-1β treated primary hPDLSCs on CD4+ T lymphocyte proliferation. Further, the expression levels of the immunomodulatory factors indoleamine-2,3-dioxygenase-1 (IDO-1), programmed cell death 1 ligand 1 (PD-L1), programmed cell death 1 ligand 2 (PD-L2), TNF-inducible gene 6 protein (TSG-6) and prostaglandin E2 (PGE2) in cytokine treated hPDLSCs were directly compared. Additionally, IDO-1, PD-L1 and prostaglandin-endoperoxide synthase 2 (PTGS-2) were inhibited pharmacologically to compare their effects on CD4+ T lymphocyte proliferation under different cytokine conditions. CD4+ T lymphocyte proliferation was significantly decreased by hPDLSCs. This effect was intensified in the presence of IL-1β and IFN-γ but not by TNF-α. IFN-γ treated hPDLSCs showed a significantly stronger inhibition of CD4+ T lymphocyte proliferation than by IL-1β treated hPDLSCs. All three inflammatory cytokines showed significant different effects on the production of immunomodulatory factors in hPDLSCs. IDO-1, PD-L1 and PD-L2 expression levels were strongest increased by IFN-γ, PTGS-2 levels mainly by IL-1β and TSG-6 by IL-1β and TNF-α to a similar extent. Additionally, pharmacological inhibition of IDO-1, PD-L1 and PTGS-2 reversed the suppression of CD4+ T lymphocyte proliferation to different extent depending on the present cytokine. This study shows that cytokines variously activate immunomodulatory mechanisms of hPDLSCs probably due to boosting the production of different immunomodulatory factors. This may be involved in fine-tuning local inflammatory processes in periodontal tissues.