## 3 Effects of Vitamin D\({}_{3}\) on Dental MSCs
### Vitamin \(D_{3}\) and Inflammatory Immunomodulatory Properties of Dental MSCs  
Vitamin D\({}_{3}\) is known to have an anti-inflammatory effect in different immune cells [72]. Dental MSCs are known to produce various inflammatory mediators and also possess immunomodulatory properties towards different immune cells [18; 19; 73; 74; 75; 76; 77]. Thus, dental MSCs are assumed to play an essential role in the inflammatory processes in the oral cavity. The basal production of different pro-inflammatory mediators by dental MSCs is rather low. It is strongly enhanced by stimulation with bacterial components, such as LPS or inflammatory cytokines like IL-1\(\beta\). Two studies investigated the effects of vitamin D\({}_{3}\) on the basal production of various inflammatory mediators. [PERSON] et al. showed that 1,25(OH)\({}_{2}\)D\({}_{3}\) inhibits the basal production of IL-8 by primary hPDLCs, but does not affect IL-6 production [78]. In contrast, [PERSON] et al. reported that 1,25(OH)\({}_{2}\)D\({}_{3}\) up-regulates the basal gene expression of IL-6 in human periodonotin cells [44]. The 1,25(OH)\({}_{2}\)D\({}_{3}\) inhibits _P. gingivalis_-induced production of IL-8 by primary hPDLCs without affecting IL-6 production [78]. [PERSON] et al. showed that both 1,25(OH)\({}_{2}\)D\({}_{3}\) and 25(OH)D\({}_{3}\) attenuate the production of IL-8 and monocyte chemoattractant protein 1 (MCP-1) in hPDLCs stimulated with _P. gingivalis_ LPS or heat-killed _P. gingivalis_[45]. The data on IL-6 were somewhat controversial: Both vitamin D\({}_{3}\) metabolites diminished IL-6 production in a commercial cell line, but not by primary cells. This observation suggests that the response of dental cells to vitamin D\({}_{3}\) might depend on the cell source [45]. [PERSON] et al. reported that 1,25(OH)\({}_{2}\)D\({}_{3}\) attenuates _Escherichia coli_ LPS-induced IL-6 and chemokine ligand 1 (CXCL-1) production by human periodontal ligament cells, but did not affect that of IL-1\(\beta\) and MCP-1. [PERSON] et al. showed that 1,25(OH)\({}_{2}\)D\({}_{3}\) inhibits the IL-1\(\beta\)-induced production of several inflammatory mediators like IL-6, IL-8, CC chemokine ligand (CCL) 20, CXC chemokine ligand (CXCL) 10, and matrix metalloproteinase (MMP)-3, but has no effect on the production of tissue inhibitor of metalloproteinases 1 [46]. This effect is associated with the suppression of c-jun N-terminal kinase (JNK) phosphorylation and inhibitor kappa B-\(\alpha\) degradation [46]. [PERSON] et al. observed various effects of 1,25(OH)\({}_{2}\)D\({}_{3}\) on the inflammatory response in hGFs and hPDLCs stimulated with _P. gingivalis_ and _Streptococcus pyogenes_. Under these conditions, 1,25(OH)\({}_{2}\)D\({}_{3}\) slightly increases IL-6 production, inhibits IL-8 and IL-12 production, and strongly promotes IL-10 production [79]. [PERSON] et al. demonstrated that 1,25(OH)\({}_{2}\)D\({}_{3}\) inhibits _P. gingivalis_-induced production of tumor necrosis factor (TNF)-\(\alpha\), IL-8, and IL-12 production by hPDLCs [80]. [PERSON] et al. reported that 1,25(OH)\({}_{2}\)D\({}_{3}\) attenuates the production of IL-6 and IL-8 in hGFs stimulated by glycated human serum albumin (HSA) or HSA + IL-1\(\beta\) or IL-1\(\beta\) + IL-17 [81]. Dental MSCs, similarly to MSCs of other tissues, possess immunomodulatory features and regulate the functional properties of various immune cells [18; 19]. The effects of MSCs on immune cells are mainly immunosuppressive. Particularly, MSCs inhibit T-cell proliferation, stimulate the differentiation of regulatory T-cells (Tregs), inhibit the activity of Th17 cells, and promote the differentiation of macrophages towards an anti-inflammatory phenotype. This immunomodulatory activity of dental MSCs is strongly activated by the inflammatory cytokines IL-1\(\beta\), TNF-\(\alpha\), and interferon (IFN)-\(\gamma\), which are produced mainly by immune cells [3; 76; 82; 83]. Thus, there is a complex interaction between dental MSCs and immune cells, in which these cell types regulate each other's activity reciprocally.