Topical Plant Polyphenols Prevent Type I Interferon Signaling in the Skin and Suppress Contact Hypersensitivity

Abstract

Human keratinocytes were recently shown to respond to anti-EGFR (epidermal growth factor receptor) drugs with activation of an interferon-κ-driven autocrine loop, leading to enhanced expression of innate antiviral effectors and of the pro-inflammatory chemokines CXCL10 (C-X-C motif chemokine 10) and CCL2 (C-C motif ligand 2). Here we showed active type I interferon signaling in the skin lesions of cancer patients undergoing treatment with the anti-EGFR drug cetuximab. Strong nuclear positivity for Interferon Regulatory Factor 1 and phosphorylated Signal Transducer and Activator of Transcription 1, enhanced interferon-κ expression and CXCL10 was associated to the epidermal compartment. Notably, 50 micromolar resveratrol and quercetin fully suppressed the low constitutive levels of type I interferon signaling and prevented its activation by the anti-EGFR cetuximab or gefitinib in cultured keratinocytes. In sensitized mice undergoing DNFB (2,4-dinitro-1-fluorobenzene)-induced contact hypersensitivity, local administration of gefitinib prior to elicitation further amplified hapten-induced type I interferon activation, tissue edema, and infiltration by T cells, whereas resveratrol or quercetin suppressed this inflammatory cascade. Overall, these data suggest that topical application of resveratrol or quercetin could be potentially effective in preventing pathological conditions due to overactivation of type I IFN (interferon)-driven circuits in the skin, including the inflammatory manifestations of anti-EGFR drug-induced skin-targeted toxicity.

Role of Resveratrol in Regulating Cutaneous Functions

“…Keratinocytes were pretreated with 20 or 100 μM resveratrol for 16 hr, followed by removal of media, and then exposed to 800 μM cumen hydroperoxide for 8 hr ↑GSH expression ↓Apoptosis ↑NRF2 activation [99] Evidence-Based Complementary and Alternative Medicine 5 Mice BALB/c mouse ears were treated topically with 10 mM resveratrol 2 hr prior to DNFB challenge ↓Ear thickness ↓CD3-positive cells ↓ICAM-1, CCL2, and CXCL10 expression ↓Interferon regulatory factor 1 and phosphorylated STAT1 [113] Following induction of allergic contact dermatitis, NC/Nga mice were treated topically with 2.5% resveratrol or resveratrol-enriched rice extract twice weekly for 5 weeks ↓Epidermal thickness ↓Dermatitis score ↓Serum IgE ↓TEWL ↑Skin hydration ND [114] BALB/c mice were orally treated with resveratrol at a dose of 10 mg/kg body weight 1 hr prior to intravenous challenge with 200 μg dinitrophenylhuman serum albumin ↓IL-4 and TNF-α ↓CD11b-positive cells ↓Tyk2-STAT1 activation [116] Atopic dermatitis-like lesions were induced by topical applications of DNFB to the back of BALB/c mice for 5 weeks, followed by orally given resveratrol at a daily dose of 30 mg/kg body weight for 1 week ↓Dermatitis scores ↓Epidermal thickness ↓Cytokine mRNA ND [117] Atopic dermatitis-like lesions were induced by topical applications of dermatophagoides farinae to the back of NC/Nga mice for 2 weeks, followed by orally given resveratrol at a daily dose of 20 mg/kg body weight for 2 weeks ↓Dermatitis scores ↓Cytokine mRNA and protein ↓High mobility group box 1 expression [118] Psoriasis-like skin lesions were induced by topical applications of imiquimod to the back of BALB/c mice, which were orally given resveratrol at a daily dose of 400 mg/ kg body weight, for 7 days.…”

“…For example, incubation of keratinocytes with 50 μM resveratrol for 3 hr lowered the expression levels of mRNA for IL-6, IL-8, TNF-α, and macrophage inflammatory protein 1 (MIF-1) by over 50% [91]. While production of proinflammatory cytokines markedly increased in keratinocytes exposed to TNF-α, lipopolysaccharide, interferon c (IFN-c), and UV irradiation [91,102,[112][113][114], addition of 50 μM resveratrol 1 hr prior to lipopolysaccharide treatment dramatically decreased mRNA levels (>40% reduction) for MIF-1, IL-6, and cyclooxygenase 2 in comparison with keratinocytes treated with lipopolysaccharide alone [91]. Yet, resveratrol also dose-dependently stimulated IL-8 production in keratinocyte cultures [91], suggesting that resveratrol differentially regulates cytokine production.…”

“…Although there is still little or no evidence that resveratrol can inhibit cutaneous inflammation in humans, anti-inflammatory benefits of resveratrol have been well demonstrated in murine models of inflammatory dermatoses. For example, in acute allergic contact dermatitis model, pretreatment of mouse ears with resveratrol reduced the density Evidence-Based Complementary and Alternative Medicine of CD3 + cells by≈90% in parallel with significant reduction of ear thickness and expression levels of intercellular adhesion molecule 1 (ICAM-1), C-X-C motif chemokine ligand 10 (CXCL10), C-C motif chemokine ligand 2 (CCL2), and IFN-κ in the epidermis [113], suggesting preventive benefits of topical resveratrol in acute allergic contact dermatitis. Moreover, the therapeutic effects of topical resveratrol have also been demonstrated in an atopic dermatitis-like disease model.…”

“…But one study showed that resveratrol increases IL-8 production in keratinocytes stimulated with a combination of TNF-α and IFNc via upregulation of aryl hydrocarbon receptor expression [91]. Inhibition of allergic contact dermatitis by resveratrol could be attributable to the downregulation of interferon regulatory factor 1/ STAT1 signaling pathway and inhibition of phosphorylation of MAPK/p38 and/or phospholipase Cc [113,116,198]. Moreover, resveratrol inhibited proliferation and differentiation of CD+ T cells and proliferation of 17 T cells via upregulation of phosphorylated MAPK and downregulation of phosphorylated mammalian target of rapamycin (p-mTOR) in Jurkat cells [199].…”

Extraction and Electrochemical Analysis of Polyphenols in Plant Samples

“…People obtain polyphenols from fruits, vegetables, flowers, tea and other plants. Polyphenols have many biological activities, such as causing weight loss, reducing blood pressure, facilitating bacteriostasis, and scavenging free radicals as well as showing anticancer, anti-inflammatory, anti-aging, antitumour, and antioxidation effects, so in-depth studies of plant polyphenols are of great interest [1][2][3][4][5][6][7][8][9]. In recent years, plant polyphenols from natural sources have been widely used as antioxidants, antimicrobial agents and preservatives due to their significant antioxidant effects [10][11][12][13][14][15][16][17].…”