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-a) 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-a-induced STAT3 phosphorylation, whereas they suppressed T/I-activated NFkappaB and constitutive and T/I-induced but not TGF-a-induced ERK1/2 phosphorylation. Vb and Qr suppressed total EGFR phosphorylation, but they synergized with TGF-a to enhance nuclear accumulation of phosphorylated EGFR. Vb strongly inhibited TGF-a-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-a 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. Antioxid. Redox Signal. 16, 314-328.

Polydatin: A review of pharmacology and pharmacokinetics

“…PD activates aryl hydrocarbon receptor machinery in UV-exposed keratinocytes through down-regulating the gene expression of pro-inflammatory cytokines/enzymes, suppressing interferon gamma-inducible protein 10 (IP-10) release, and up-regulating IL-8 level (Potapovich et al, 2011), opposing enhanced monocyte chemotactic protein-1 (MCP-1) and IP-10 transcription/synthesis (Pastore et al, 2012). PD is also able to modulate IL-6, IL-8 and TNF-a gene expression, increase the release of human b-defensin 2 and gene expression of heat shock protein 70B 0 in heat-stressed HaCaT (Ravagnan et al, 2013).…”

Antioxidant activity of various extracts of selected gourd vegetables

“…Olive oil phenolics have been found to decrease the cardiovascular mortality (Keys et al 1986;Covas et al 2006). The beneficial effects of polyphenols in skin applications as antiinflammatory agents has been ascribed to the capacity of polyphenols in altering signal transduction and epigenetic regulation of gene expression (Pastore et al 2011;Pastore et al 2012;Rhodes et al 2013). Another indirect way through which polyphenols may exert antioxidative protection is that these bioactive compounds might increase gene transcription of a factor that regulates enzymes involved in the antioxidant function (Na and Surh 2008).…”

Resveratrol Induces Long-Lasting IL-8 Expression and Peculiar EGFR Activation/Distribution in Human Keratinocytes: Mechanisms and Implications for Skin Administration

“…At the same time, deregulating or damaging effects towards normal cells/tissues should be minimal. While the majority of mechanistic studies demonstrate that Resv selectively affects aberrant molecular pathways in tumor cells, there is emerging evidence that normal cells such as endotheliocytes, lymphocytes, smooth muscle cells, chondrocytes, tendocytes [2], [8], [14], adipocytes [15], [16], neurons [17], osteoblasts, hepatic cells, and epidermal keratinocytes [18]–[20] are vulnerable to Resv as well.…”