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

AIMS:

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.

INNOVATION:

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.

CONCLUSION:

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: Saveria Pastore, Daniela Lulli, Paolo Fidanza, Alla I Potapovich, Vladimir A Kostyuk, Chiara De Luca, Elena Mikhal'chik, Liudmila G Korkina
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 16 Issue 4 Pg. 314-28 (Feb 15 2012) ISSN: 1557-7716 [Electronic] United States
• PMID: 21967610 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Chemokines
• Polyphenols
• Superoxides
• ErbB Receptors

Topics

• Animals
• Antioxidants (pharmacology)
• Cell Nucleus (drug effects, metabolism)
• Cells, Cultured
• Chemokines (biosynthesis, metabolism)
• Cytoplasm (drug effects, metabolism)
• ErbB Receptors (metabolism)
• Humans
• Keratinocytes (cytology, drug effects, metabolism)
• Phosphorylation
• Polyphenols (pharmacology)
• Rats
• Rats, Wistar
• Superoxides (pharmacology)
• Wound Healing (drug effects)