{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T21:03:48Z","timestamp":1767474228588,"version":"build-2065373602"},"reference-count":54,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2018,9,6]],"date-time":"2018-09-06T00:00:00Z","timestamp":1536192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Human keratinocytes were recently shown to respond to anti-EGFR (epidermal growth factor receptor) drugs with activation of an interferon-\u03ba-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-\u03ba 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.<\/jats:p>","DOI":"10.3390\/ijms19092652","type":"journal-article","created":{"date-parts":[[2018,9,7]],"date-time":"2018-09-07T11:47:41Z","timestamp":1536320861000},"page":"2652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Topical Plant Polyphenols Prevent Type I Interferon Signaling in the Skin and Suppress Contact Hypersensitivity"],"prefix":"10.3390","volume":"19","author":[{"given":"Maria Luigia","family":"Carbone","sequence":"first","affiliation":[{"name":"Laboratory of Experimental Immunology, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela","family":"Lulli","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Passarelli","sequence":"additional","affiliation":[{"name":"Pathology Unit, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saveria","family":"Pastore","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, IDI-IRCCS, 00167 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,9,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3389\/fimmu.2017.00209","article-title":"Evolution of interferons and interferon receptors","volume":"8","author":"Secombes","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Negishi, H., Taniguchi, T., and Yanai, H. (2017). The interferon (IFN) class of cytokines and the IFN regulatory factor (IRF) transcription factor family. Cold Spring Harb. Perspect. Biol., pii:A028423.","DOI":"10.1101\/cshperspect.a028423"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2014","journal-title":"Nat. Rev. Immunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39765","DOI":"10.1074\/jbc.M102502200","article-title":"Interferon-\u03ba, a novel type I interferon expressed in human keratinocytes","volume":"276","author":"LaFleur","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4822","DOI":"10.4049\/jimmunol.169.9.4822","article-title":"Regulatory effect of IFN-\u03ba, a novel type I IFN, on cytokine production by cells of the innate immune system","volume":"169","author":"Nardelli","year":"2002","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1007\/s00204-014-1244-4","article-title":"Epidermal growth factor receptor signalling in keratinocyte biology: Implications for skin toxicity of tyrosine kinase inhibitors","volume":"88","author":"Pastore","year":"2014","journal-title":"Arch. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47777","DOI":"10.18632\/oncotarget.10013","article-title":"Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin","volume":"7","author":"Lulli","year":"2016","journal-title":"Oncotarget"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Lulli, D., Carbone, M.L., and Pastore, S. (2017). The MEK inhibitors trametinib and cobimetinib induce a type I interferon response in human keratinocytes. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102227"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0002-9440(10)63654-1","article-title":"Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation","volume":"163","author":"Mascia","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5047","DOI":"10.4049\/jimmunol.174.8.5047","article-title":"ERK1\/2 regulates epidermal chemokine expression and skin inflammation","volume":"174","author":"Pastore","year":"2005","journal-title":"J. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrm3801","article-title":"Cellular mechanisms and physiological consequences of redox-dependent signalling","volume":"15","author":"Finkel","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3109\/08830185.2012.755176","article-title":"Reactive oxygen species in the immune system","volume":"32","author":"Yang","year":"2013","journal-title":"Int. Rev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Olagnier, D., Peri, S., Steel, C., van Montfoort, N., Chiang, C., Beljanski, V., Slifker, M., He, Z., Nichols, C.N., and Lin, R. (2014). Cellular oxidative stress response controls the antiviral and apoptotic programs in dengue virus-infected dendritic cells. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004566"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"ra115","DOI":"10.1126\/scisignal.aaf1933","article-title":"Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus","volume":"9","author":"Buskiewicz","year":"2016","journal-title":"Sci. Signal."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1089\/ars.2017.7364","article-title":"Transinflammation: How innate immune activation and free radicals drive nuclear reprogramming","volume":"29","author":"Meng","year":"2018","journal-title":"Antioxid. Redox Signal."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/1485283","article-title":"Reactive oxygen species-mediated mechanisms of action of targeted cancer therapy","volume":"2017","author":"Teppo","year":"2017","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.canlet.2016.07.020","article-title":"ASCT2 (SLC1A5) is an EGFR-associated protein that can be co-targeted by cetuximab to sensitize cancer cells to ROS-induced apoptosis","volume":"381","author":"Lu","year":"2016","journal-title":"Cancer Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9101","DOI":"10.1074\/jbc.M114.631580","article-title":"Gefitinb-mediated reactive oxygen species (ROS) instigates mitochondrial dysfunction and drug resistance in lung cancer cells","volume":"290","author":"Okon","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1080\/10408390903584094","article-title":"Effects of flavonoids and other polyphenols on inflammation","volume":"51","author":"Ballester","year":"2011","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"823","DOI":"10.2174\/138955711796575489","article-title":"Plant phenylpropanoids as emerging anti-inflammatory agents","volume":"11","author":"Korkina","year":"2011","journal-title":"Mini Rev. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.taap.2011.06.007","article-title":"Plant polyphenols differentially modulate inflammatory responses of human keratinocytes by interfering with activation of transcription factors NF\u03baB and AhR and EGFR-ERK pathway","volume":"255","author":"Potapovich","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1089\/ars.2011.4053","article-title":"Plant polyphenols regulate chemokine expression and tissue repair in human keratinocytes through interaction with cytoplasmic and nuclear components of epidermal growth factor receptor system","volume":"16","author":"Pastore","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.ejphar.2007.03.051","article-title":"Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-\u03b3","volume":"566","author":"Maiuri","year":"2007","journal-title":"Eur. J. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.bbrc.2012.12.093","article-title":"Resveratrol suppresses tumor progression via the regulation of indoleamine 2,3-dioxygenase","volume":"431","author":"Noh","year":"2013","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Serra, D., Rufino, A.T., Mendes, A.F., Almeida, L.M., and Dinis, T.C. (2014). Resveratrol modulates cytokine-induced Jak\/STAT activation more efficiently than 5-aminosalicylic acid: An in vitro approach. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0109048"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1007\/s00011-006-5141-z","article-title":"Gene expression profiling of skin and draining lymph nodes of rats affected with cutaneous contact hypersensitivity","volume":"55","author":"Hartmann","year":"2006","journal-title":"Inflamm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1016\/j.jaci.2007.09.015","article-title":"Signal transducer and activator of transcription 1 decoy oligodeoxynucleotide suppression of contact hypersensitivity","volume":"121","author":"Wagner","year":"2008","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nri3150","article-title":"Early immune events in the induction of allergic contact dermatitis","volume":"12","author":"Kaplan","year":"2012","journal-title":"Nat. Rev. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/jid.2009.336","article-title":"EGFR regulates the expression of keratinocyte-derived granulocyte\/macrophage colony-stimulating factor in vitro and in vivo","volume":"130","author":"Mascia","year":"2010","journal-title":"J. Investig. Dermatol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.gene.2015.09.058","article-title":"The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases","volume":"576","author":"Niewold","year":"2016","journal-title":"Gene"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1840","DOI":"10.1002\/art.40166","article-title":"Enhanced inflammasome activity in systemic lupus erythematosus is mediated via type I interferon-induced up-regulation of Interferon Regulatory Factor 1","volume":"69","author":"Liu","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/j.jid.2016.09.008","article-title":"Lupus skin is primed for IL-6 inflammatory responses through a keratinocyte-mediated autocrine type I interferon loop","volume":"37","author":"Stannard","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1089\/jir.2006.26.133","article-title":"Analysis of IFN-\u03ba expression in pathologic skin conditions: Downregulation in psoriasis and atopic dermatitis","volume":"26","author":"Scarponi","year":"2006","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_34","first-page":"e23820","article-title":"The regulation of inflammation by interferons and their STATs","volume":"2","author":"Rauch","year":"2013","journal-title":"JAKSTAT"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1016\/S0002-9440(10)63986-7","article-title":"Differential and sequential expression of multiple chemokines during elicitation of allergic contact hypersensitivity","volume":"158","author":"Goebeler","year":"2001","journal-title":"Am. J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e1004969","DOI":"10.1080\/23723556.2015.1004969","article-title":"Mechanisms underlying skin disorders induced by EGFR inhibitors","volume":"2","author":"Holcmann","year":"2015","journal-title":"Mol. Cell. Oncol."},{"key":"ref_37","first-page":"127","article-title":"Correlation of cetuximab-induced skin rash and outcomes of solid tumor patients treated with cetuximab: A systematic review and meta-analysis","volume":"9","author":"Fouad","year":"2015","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s12263-009-0148-z","article-title":"Improving the oral bioavailability of beneficial polyphenols through designed synergies","volume":"5","author":"Scheepens","year":"2010","journal-title":"Genes Nutr."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1818","DOI":"10.1089\/ars.2012.4581","article-title":"Dietary (poly)phenolics in human health: Structures, bioavailability, and evidence of protective effects against chronic diseases","volume":"18","author":"Spencer","year":"2013","journal-title":"Antioxid. Redox Signal."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ijpharm.2016.09.014","article-title":"Effect of quercetin and resveratrol co-incorporated in liposomes against inflammatory\/oxidative response associated with skin cancer","volume":"513","author":"Caddeo","year":"2016","journal-title":"Int. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.abb.2010.12.030","article-title":"The grape antioxidant resveratrol for skin disorders: Promise, prospects, and challenges","volume":"508","author":"Ndiaye","year":"2011","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"392","DOI":"10.3389\/fphar.2018.00392","article-title":"Natural antioxidants: Multiple mechanisms to protect skin from solar radiation","volume":"9","author":"Dunaway","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Murakami, I., Chaleckis, R., Pluskal, T., Ito, K., Hori, K., Ebe, M., Yanagida, M., and Kondoh, H. (2014). Metabolism of skin-absorbed resveratrol into its glucuronized form in mouse skin. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115359"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"6815","DOI":"10.4049\/jimmunol.0903991","article-title":"Immunosuppressive effect of quercetin on dendritic cell activation and function","volume":"184","author":"Huang","year":"2010","journal-title":"J. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.addr.2012.02.011","article-title":"Breaching the skin barrier-insights from molecular simulation of model membranes","volume":"65","author":"Notman","year":"2013","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Bonechi, C., Martini, S., Ciani, L., Lamponi, S., Rebmann, H., Rossi, C., and Ristori, S. (2012). Using liposomes as carriers for polyphenolic compounds: The case of trans-resveratrol. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041438"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.ijpharm.2012.08.009","article-title":"Nanocarriers for topical administration of resveratrol: A comparative study","volume":"440","author":"Scognamiglio","year":"2013","journal-title":"Int. J. Pharm."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s13346-016-0350-7","article-title":"Skin targeting of resveratrol utilizing solid lipid nanoparticle-engrossed gel for chemically induced irritant contact dermatitis","volume":"7","author":"Shrotriya","year":"2017","journal-title":"Drug Deliv. Transl. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.ejpb.2016.08.011","article-title":"Quercetin topical application, from conventional dosage forms to nanodosage forms","volume":"108","author":"Hatahet","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.tifs.2016.07.004","article-title":"The biological activities, chemical stability, metabolism and delivery systems of quercetin: A review","volume":"56","author":"Wang","year":"2016","journal-title":"Trends Food Sci. Technol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.1468-3083.2011.04414.x","article-title":"Resveratrate protects human skin from damage due to the repetitive ultraviolet irradiation","volume":"27","author":"Wu","year":"2013","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1177\/1535370217723628","article-title":"Human skin gene expression: Natural (trans)resveratrol versus five resveratrol analogs for dermal applications","volume":"242","author":"Lephart","year":"2017","journal-title":"Exp. Biol. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1172\/JCI119496","article-title":"Granulocyte macrophage-colony stimulating factor is overproduced by keratinocytes in atopic dermatitis. Implications for sustained dendritic cell activation in the skin","volume":"99","author":"Pastore","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real time RT-PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2652\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:19:15Z","timestamp":1760195955000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/9\/2652"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,6]]},"references-count":54,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2018,9]]}},"alternative-id":["ijms19092652"],"URL":"https:\/\/doi.org\/10.3390\/ijms19092652","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2018,9,6]]}}}