title: Plant polyphenols regulate chemokine expression and tissue repair in human keratinocytes through interaction with cytoplasmic and nuclear components of epidermal growth factor receptor system.
abstract: OBJECTIVE
  To evaluate mechanisms underlying modulation of inflammatory chemokines in primary human keratinocytes (normal human epidermal keratinocytes) and repair-related processes in wound models by plant polyphenols (PPs) with antioxidant and superoxide scavenging properties (verbascoside [Vb], resveratrol [Rv], polydatin [Pd], quercetin [Qr], and rutin).
  
  
  RESULTS
  Epidermal growth factor receptor (EGFR)-controlled chemokines CXCL8/interleukin 8 (IL-8), CCL2/monocyte chemotactic protein-1 (MCP-1), and CXCL10/interferon gamma-produced protein of 10 kDa (IP-10) were modulated by transforming growth factor alpha (TGF-α) and by the tumor necrosis factor alpha/interferon gamma combination (T/I). EGFR phosphorylation, nuclear translocation, and downstream cytoplasmic signaling pathways (extracellular regulation kinase [ERK]1/2, p38, STAT3, and PI-3K) were studied. All PPs did not affect TGF-α-induced STAT3 phosphorylation, whereas they suppressed T/I-activated NFkappaB and constitutive and T/I-induced but not TGF-α-induced ERK1/2 phosphorylation. Vb and Qr suppressed total EGFR phosphorylation, but they synergized with TGF-α to enhance nuclear accumulation of phosphorylated EGFR. Vb strongly inhibited TGF-α-induced p38 phosphorylation and T/I-induced NFkappaB and activator protein-1 (AP-1) binding to DNA. Vb was an effective inhibitor of T/I-stimulated chemokine synthesis, and it accelerated scratch wound healing in vitro. Anti-inflammatory and wound healing activities of Vb were confirmed in vivo in the full-thickness excision wound. Although Pd and Rv did not affect EGFR activation/translocation, they and Qr synergized with TGF-α and T/I in the induction of IL-8 transcription/synthesis while opposing enhanced MCP-1 and IP-10 transcription/synthesis connected with pharmacologically impaired EGFR functioning.
  
  
  METHODS
  PPs perturb the EGFR system in human keratinocytes, and this effect may be implicated in the regulation of inflammatory and repair-related processes in the skin.
  
  
  CONCLUSIONS
  Anti-inflammatory and wound healing effects of PPs depend on their interaction with EGFR-controlled cytoplasmic and nuclear pathways rather than on their direct redox properties.
authors.affiliation: Tissue Engineering & Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Rome, Italy.
authors.forename: Saveria
authors.initials: S
authors.lastname: Pastore
authors.forename: Daniela
authors.initials: D
authors.lastname: Lulli
authors.forename: Paolo
authors.initials: P
authors.lastname: Fidanza
authors.forename: Alla I
authors.initials: AI
authors.lastname: Potapovich
authors.forename: Vladimir A
authors.initials: VA
authors.lastname: Kostyuk
authors.forename: Chiara
authors.initials: C
authors.lastname: De Luca
authors.forename: Elena
authors.initials: E
authors.lastname: Mikhal'chik
authors.forename: Liudmila G
authors.initials: LG
authors.lastname: Korkina
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis* / Q000378:metabolism; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D059808:Polyphenols / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000494:pharmacology; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D018925:Chemokines; D059808:Polyphenols; D013481:Superoxides; D066246:ErbB Receptors