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Int. J. Mol. Sci. 2018, 19(9), 2652; https://doi.org/10.3390/ijms19092652

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

1
Laboratory of Experimental Immunology, IDI-IRCCS, 00167 Rome, Italy
2
Pathology Unit, IDI-IRCCS, 00167 Rome, Italy
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 29 August 2018 / Accepted: 4 September 2018 / Published: 6 September 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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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. View Full-Text
Keywords: EGFR; cetuximab; gefitinib; interferon κ; CXCL10; CCL2; resveratrol; quercetin EGFR; cetuximab; gefitinib; interferon κ; CXCL10; CCL2; resveratrol; quercetin
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Carbone, M.L.; Lulli, D.; Passarelli, F.; Pastore, S. Topical Plant Polyphenols Prevent Type I Interferon Signaling in the Skin and Suppress Contact Hypersensitivity. Int. J. Mol. Sci. 2018, 19, 2652.

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