Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF{kappa}B and AhR and EGFR-ERK pathway

Journal Article · Thu Sep 01 00:00:00 EDT 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2011.06.007· OSTI ID:21587830

Potapovich, Alla I ^[1]; Lulli, Daniela; Fidanza, Paolo ^[1]; Kostyuk, Vladimir A ^[1]; De Luca, Chiara; Pastore, Saveria ^[1]

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1. Tissue Engineering and Skin Pathophysiology Laboratory, Dermatology Research Institute (IDI IRCCS), Via Monti di Creta 104, Rome 00167 (Italy)

Molecular mechanisms underlying modulation of inflammatory responses in primary human keratinocytes by plant polyphenols (PPs), namely the glycosylated phenylpropanoid verbascoside, the stilbenoid resveratrol and its glycoside polydatin, and the flavonoid quercetin and its glycoside rutin were evaluated. As non-lethal stimuli, the prototypic ligand for epidermal growth factor receptor (EGFR) transforming growth factor alpha (TGFalpha), the combination of tumor necrosis factor (TNFalpha) and interferon (IFNgamma) (T/I), UVA + UVB irradiation, and bacterial lipopolysaccharide (LPS) were used. We demonstrated differential modulation of inflammatory responses in keratinocytes at signal transduction, gene transcription, and protein synthesis levels as a function of PP chemical structure, the pro-inflammatory trigger used, and PP interaction with intracellular detoxifying systems. The PPs remarkably inhibited constitutive, LPS- and T/I-induced but not TGFalpha-induced ERK phosphorylation. They also suppressed NFkappaB activation by LPS and T/I. Verbascoside and quercetin invariably impaired EGFR phosphorylation and UV-associated aryl hydrocarbon receptor (AhR)-mediated signaling, while rutin, polydatin and resveratrol did not affect EGFR phosphorylation and further activated AhR machinery in UV-exposed keratinocytes. In general, PPs down-regulated gene expression of pro-inflammatory cytokines/enzymes, except significant up-regulation of IL-8 observed under stimulation with TGFalpha. Both spontaneous and T/I-induced release of IL-8 and IP-10 was suppressed, although 50 {mu}M resveratrol and polydatin up-regulated IL-8. At this concentration, resveratrol activated both gene expression and de novo synthesis of IL-8 and AhR-mediated mechanisms were involved. We conclude that PPs differentially modulate the inflammatory response of human keratinocytes through distinct signal transduction pathways, including AhR and EGFR. - Graphical abstract: Display Omitted Highlights: > Effects of plant polyphenols on inflammatory responses in human keratinocytes. > Inflammatory stimuli used: TGFalpha, TNFalpha+IFNgamma, UVA+UVB, and LPS. > Inflammatory pathways connected with NFB, ERK1/2, EGFR, and AhR were investigated. > Plant polyphenols, flavonoids, stilbenoids, and phenylpropanoids, were studied. > Modulation of inflammation depends on phenolic core structure and glycosylation.

• OSTI ID: 21587830
• Journal Information: Toxicology and Applied Pharmacology, Vol. 255, Issue 2; Other Information: DOI: 10.1016/j.taap.2011.06.007; PII: S0041-008X(11)00225-0; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ENZYMES
GENES
GLYCOSIDES
HYDROCARBONS
INFLAMMATION
INTERFERON
IRRADIATION
PHOSPHORYLATION
QUERCETIN
STIMULATION
STIMULI
SYNTHESIS
AROMATICS
CARBOHYDRATES
CHEMICAL REACTIONS
FLAVONES
FLAVONOIDS
GROWTH FACTORS
HETEROCYCLIC COMPOUNDS
HETEROCYCLIC OXYGEN COMPOUNDS
HYDROXY COMPOUNDS
LYMPHOKINES
MITOGENS
ORGANIC COMPOUNDS
ORGANIC OXYGEN COMPOUNDS
PATHOLOGICAL CHANGES
PHENOLS
POLYPHENOLS
PROTEINS
PYRANS
SYMPTOMS