Targeting MAPK (p38, ERK, JNK) and inflammatory CK (GDF-15, GM-CSF) in UVB-Activated Human Skin Cells with Vitis vinifera Seed Extract

J Environ Pathol Toxicol Oncol. 2018;37(3):261-272. doi: 10.1615/JEnvironPatholToxicolOncol.2018027009.


Ultraviolet B radiation (UVB) activates mitogen-activated protein kinases (MAPK): p38, extracellular signal regulated (ERK), and c-Jun N-terminal (JNK) kinases in human skin cells. Human keratinocytes (KC) exposed to UVB secrete several cytokines (CK), among which the growth differentiation factor-15 (GDF-15) is augmented in inflammatory and aging processes and the granulocyte macrophage-colony stimulating factor (GM-CSF) is involved in cell proliferation, differentiation, and survival, and both CK have implications in skin carcinogenesis. We assessed p38, ERK, JNK, GDF-15, and GM-CSF in UVB-exposed skin cells and a red grape (Vitis vinifera) seed extract's (GSE) capacities to regulate these pathways in UVB-exposed KC. Two concentrations of the GSE extract were selected: GSE1 (37.5 μgEqGA/mL) and GSE2 (75 μgEqGA/mL) and a UVB dose (100 mJ/cm2) within the physiological range. Molecules were assessed with ELISA, semiquantitative results being confirmed by Western blot. UVB triggered the signaling molecules' phosphorylation and the concentrations of CK. All molecules but GM-CSF increased early, at 2 h, from UVB exposure while GM-CSF increased later (at 8 h). MAPK and GDF-15 were regulated by GSE1; GM-CSF, by the higher concentration, GSE2. The amplitude and kinetics of the responses were diverse according to time point, molecules, and the extract's concentration. GSE exerted beneficial effects on MAPK and CK triggered by UVB in human skin cells: reduction of phosphorylation of the assessed signaling molecules and anti-inflammatory effects. Targeting MAPK and specific inflammatory mediators such as GDF-15 and GM-CSF with GSE in UVB-induced skin cells represents a novel and a promising starting point for future photoprotection strategies.

MeSH terms

  • Cell Line, Transformed
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Growth Differentiation Factor 15 / metabolism*
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism*
  • Keratinocytes / radiation effects
  • MAP Kinase Kinase 4 / metabolism
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / radiation effects
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Plant Extracts / pharmacology*
  • Seeds / chemistry
  • Skin / cytology
  • Skin / drug effects*
  • Skin / metabolism*
  • Skin / radiation effects
  • Ultraviolet Rays
  • Vitis / chemistry*
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • GDF15 protein, human
  • Growth Differentiation Factor 15
  • Plant Extracts
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase 4