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Philips et al. Plast Aesthet Res 2022;9:4 https://dx.doi.org/10.20517/2347-9264.2021.83 Page 5 of 10

Cellular inflammation is also associated with increased production of angiogenic factors, such as vascular
endothelial growth factor (VEGF), transforming growth factor-β (TGF-β), and IL-8 [20,21] . VEGF binds to
receptor tyrosine kinase to activate the mitogen-activated protein kinase (MAPK) pathway and thereby the
[34]
activation of several transcription factors such as c-fos . TGF-β binds to its receptors to activate SMADs
that regulate the expression of cell cycle and the ECM . Finally, IL-8 binds to its chemokine receptors and
[34]
mediates its effects through several means, including the increase in intracellular calcium levels [44,45] .

Both innate and adaptive immunity are regulated by VD . VD deficiency, as well as that of its receptor, is
[49]
associated with inflammation, increased serum levels of inflammatory factors, and inflammatory
diseases [50,51] . VD supplementation inhibits the activity of NF-κB in peritoneal macrophages . VD inhibits
[52]
angiogenesis in vivo and in vitro by decreasing IL-8 expression in human fibroblasts [53,54] . It also decreases
the levels of IL-1 and IL-8 in UVA-irradiated fibroblasts, but not in UVB-irradiated or non-irradiated
fibroblasts, suggesting that VD specifically curbs inflammatory reactions to UVA exposure . Additionally,
[34]
VD inhibits the expression of the inflammatory mediators IL-1 and TNF-α, and the angiogenesis factors
TGF-β and VEGF at protein and mRNA levels in melanoma cells, implicating transcriptional regulation .
[35]
The stated conclusions on the effects of VD on the inflammatory factors have been determined through in
vitro experiments, in which non-irradiated, UVA-radiated, or UVB-radiated human dermal fibroblasts, and
melanoma cells were incubated with different concentrations of VD [34,35] . The culture media were examined
by ELISA for protein levels of the inflammatory and angiogenic factors IL-1, IL-8, TNF-α, TGF-β, and
VEGF. mRNA levels of these inflammatory and angiogenic factors were measured by reverse transcriptase-
quantitative polymerase chain reaction (RT-qPCR).

Cell viability
[55]
Cellular oxidative damage causes cell death through the intrinsic apoptosis pathway , whereas
inflammatory players cause cell death via extrinsic apoptosis . Conversely, oxidative effects and
[56]
inflammatory mediators facilitate resistance to cell death through mutations in protooncogenes or tumor
suppressor genes, or through the activation of the protein kinase B (PKB) pathway.

DNA damage activates ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-
related protein), leading to p53 activation [44,57,58] . Then p53 activates the pro-apoptotic factor Bax, allowing
the release of cytochrome C into the cytoplasm and the subsequent activation of caspases [35,44] . Also, the
increase in p53 activity activates p21 triggering its binding to cyclin-dependent kinases to cause cell cycle
[59]
[44]
arrest . Conversely, mutations in p53, due to oxidative damage, facilitate carcinogenesis .
Inflammatory cytokines are implicated in the extrinsic apoptotic pathway by activating Fas-associated death
domain and TNF receptor-associated death domain. These cause the release of Bax from Bcl-2
(antiapoptotic protein) in the mitochondrial membrane and, therefore, the activation of the caspases [44,60] .
Conversely, activation of the PKB pathway retains the binding of Bcl-2 to Bax in the resistance to
apoptosis [44,60] .

VD increases the viability of UVB radiated fibroblasts and the p53 promoter activity in melanoma cells,
suggesting cell-specific protective effects [Figure 2] [34,35] . VDR knock-out mice display reduced expression of
p53 and premature aging . The supplementation of VD results in an increase of p53 expression and
[61]
photoprotection . p53 promoter activity has been assessed by co-transfecting cells with p53 promoter
[62]
cDNA linked to firefly luciferase and thymidine kinase (TK) promoter linked to renilla luciferase (to
normalize transfection efficiency) and measuring luciferase activity following supplementation with VD .
[35]