{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:51:28Z","timestamp":1790801488708,"version":"4.1.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Interleukin (IL)-37 suppresses systemic and local inflammation. It is expressed in the epidermis, the external layer of the skin, and is decreased in inflammatory skin diseases including atopic dermatitis (AD) and psoriasis. Therefore, an agent applied topically on the skin that can increase IL-37 could be promising for treating AD and psoriasis; however, the mechanism regulating IL-37 remains largely unknown. Given that IL-37 expression is induced in differentiated keratinocytes, a major component of the epidermis, and that activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, promotes keratinocyte differentiation, we hypothesized that AHR might be involved in the IL-37 expression in human keratinocytes. We analyzed normal epidermal human keratinocytes (NHEKs) treated with tapinarof and\n                    <jats:italic>Galactomyces<\/jats:italic>\n                    ferment filtrate (GFF), which are potent AHR modulators. We found that tapinarof and GFF upregulated IL-37 in NHEKs, which was canceled by the knockdown of AHR using siRNA transfection, indicating that AHR mediates IL-37 expression in NHEKs. Furthermore, we found that the knockdown of IL-37 resulted in the upregulation of IL-33, an alarmin cytokine with crucial roles in the pathogenesis of AD and psoriasis. These findings suggest that IL-37 negatively regulates IL-33 expression in NHEKs. Finally, we examined whether tapinarof and GFF treatment modulates IL-33 expression in NHEKs. Such treatment inhibited IL-33 expression, which was partially reversed by the knockdown of either AHR or IL-37. Taken together, our findings provide the first evidence that tapinarof and GFF could have potential to prevent IL-33-overexpressing disorders such as AD and psoriasis\n                    <jats:italic>via<\/jats:italic>\n                    the AHR\/IL-37 axis.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2022.745997","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T08:48:04Z","timestamp":1652950084000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR\/IL-37 Axis in Human Keratinocytes"],"prefix":"10.3389","volume":"13","author":[{"given":"Gaku","family":"Tsuji","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akiko","family":"Hashimoto-Hachiya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoyo","family":"Matsuda-Taniguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Takai-Yumine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Takemura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masutaka","family":"Furue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Nakahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1944","article-title":"IL-37 Is a Fundamental Inhibitor of Innate Immunity","volume":"11","author":"Nold","year":"2010","journal-title":"Nat Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-019-0277-8","article-title":"The IL-1 Family of Cytokines and Receptors in Rheumatic Diseases","volume":"15","author":"Dinarello","year":"2019","journal-title":"Nat Rev Rheumatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"83","DOI":"10.2119\/molmed.2017.00022","article-title":"IL-37 Suppresses MyD88-mediated Inflammatory Responses in Human Aortic Valve Interstitial Cells","volume":"23","author":"Zhan","year":"2017","journal-title":"Mol Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cjca.2019.04.007","article-title":"Role of IL-37 in Cardiovascular Disease Inflammation","volume":"35","author":"Yang","year":"2019","journal-title":"Can J Cardiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02482","article-title":"Interleukin-37 Ameliorates Influenza Pneumonia by Attenuating Macrophage Cytokine Production in a MAPK-dependent Manner","volume":"10","author":"Qi","year":"2019","journal-title":"Front Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3103","article-title":"IL-37 Requires the Receptors IL-18R\u03b1 and IL-1R8 (SIGIRR) to Carry Out its Multifaceted Anti-Inflammatory Program Upon Innate Signal Transduction","volume":"16","author":"Nold-Petry","year":"2015","journal-title":"Nat Immunol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/1346-8138.15664","article-title":"Basics and Recent Advances in the Pathophysiology of Atopic Dermatitis","volume":"48","author":"Nakahara","year":"2021","journal-title":"J Dermatol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00752","article-title":"IL-37 Ameliorating Allergic Inflammation in Atopic Dermatitis Through Regulating Microbiota and AMPK-mTOR Signaling Pathway-Modulated Autophagy Mechanism","volume":"11","author":"Hou","year":"2020","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/all.14769","article-title":"Skewed Inflammation is Associated With Aberrant interleukin-37 Signaling Pathway in Atopic Dermatitis","volume":"76","author":"Hou","year":"2021","journal-title":"Allergy"},{"key":"B10","doi-asserted-by":"publisher","first-page":"5","DOI":"10.2340\/00015555-2808","article-title":"Highlighting interleukin-36 Signaling in Plaque Psoriasis and Pustular Psoriasis","volume":"98","author":"Furue","year":"2018","journal-title":"Acta Derm Venereol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.23736\/S0392-0488.18.06202-8","article-title":"Psoriasis and the TNF\/IL23\/IL17 Axis","volume":"154","author":"Furue","year":"2019","journal-title":"G Ital Dermatol Venereol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2000083","article-title":"IL-37 Expression Is Downregulated in Lesional Psoriasis Skin","volume":"4","author":"R\u00f8nholt","year":"2020","journal-title":"Immunohorizons"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2015.08.002","article-title":"Expression of IL-36 Family Cytokines and IL-37 But Not IL-38 Is Altered in Psoriatic Skin","volume":"80","author":"Keermann","year":"2015","journal-title":"J Dermatol Sci"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20215424","article-title":"Aryl Hydrocarbon Receptor in Atopic Dermatitis and Psoriasis","volume":"20","author":"Furue","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2020.10.085","article-title":"Tapinarof in the Treatment of Psoriasis: A Review of the Unique Mechanism of Action of a Novel Therapeutic Aryl Hydrocarbon Receptor-Modulating Agent","volume":"84","author":"Bissonnette","year":"2021","journal-title":"J Am Acad Dermatol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2020.05.135","article-title":"Efficacy and Patient-Reported Outcomes From a Phase 2b, Randomized Clinical Trial of Tapinarof Cream for the Treatment of Adolescents and Adults With Atopic Dermatitis","volume":"84","author":"Paller","year":"2021","journal-title":"J Am Acad Dermatol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2020.04.181","article-title":"A Phase 2b, Randomized Clinical Trial of Tapinarof Cream for the Treatment of Plaque Psoriasis: Secondary Efficacy and Patient-Reported Outcomes","volume":"84","author":"Stein Gold","year":"2021","journal-title":"J Am Acad Dermatol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21249412","article-title":"IL-24 Negatively Regulates Keratinocyte Differentiation Induced by Tapinarof, An Aryl Hydrocarbon Receptor Modulator: Implication in the Treatment of Atopic Dermatitis","volume":"21","author":"Vu","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/ced.12635","article-title":"Galactomyces Fermentation Filtrate Prevents T Helper 2-Mediated Reduction of Filaggrin in an Aryl Hydrocarbon Receptor-Dependent Manner","volume":"40","author":"Takei","year":"2015","journal-title":"Clin Exp Dermatol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2340\/00015555-3003","article-title":"Antioxidative Phytochemicals Accelerate Epidermal Terminal Differentiation","volume":"98","author":"Furue","year":"2018","journal-title":"Acta Derm Venereol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2014.28","article-title":"Transcriptome Analysis of Psoriasis in a Large Case-Control Sample: RNA-seq Provides Insights Into Disease Mechanisms","volume":"134","author":"Li","year":"2014","journal-title":"J Invest Dermatol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"17446","DOI":"10.1038\/s41598-017-17782-4","article-title":"Epidermal Cornification is Preceded by the Expression of a Keratinocyte-Specific Set of Pyroptosis-Related Genes","volume":"7","author":"Lachner","year":"2017","journal-title":"Sci Rep"},{"key":"B23","doi-asserted-by":"publisher","first-page":"6085801","DOI":"10.1155\/2019\/6085801","article-title":"PG102 Upregulates IL-37 Through P38, ERK, and Smad3 Pathways in HaCaT Keratinocytes","volume":"2019","author":"Kim","year":"2019","journal-title":"Mediators Inflamm"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9030891","article-title":"Aryl Hydrocarbon Receptor Activation Downregulates IL-33 Expression in Keratinocytes Via Ovo-Like 1","volume":"9","author":"Tsuji","year":"2020","journal-title":"J Clin Med"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13309","article-title":"Interleukin-37 Improves T-cell-mediated Immunity and Chimeric Antigen Receptor T-cell Therapy in Aged Backgrounds","volume":"20","author":"Hamilton","year":"2021","journal-title":"Aging Cell"},{"key":"B26","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.toxlet.2015.02.007","article-title":"Cynaropicrin Attenuates UVB-induced Oxidative Stress","volume":"234","author":"Takei","year":"2015","journal-title":"Toxicol Lett"},{"key":"B27","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1038\/jid.2011.194","article-title":"Identification of Ketoconazole as an AhR-Nrf2 Activator in Cultured Human Keratinocytes: The Basis of its Anti-Inflammatory Effect","volume":"132","author":"Tsuji","year":"2012","journal-title":"J Invest Dermatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100577","article-title":"Aberrant HO-1\/NQO1-reactive Oxygen species-ERK Signaling Pathway Contributes to Aggravation of TPA-induced Irritant Contact Dermatitis in Nrf2-deficient Mice","volume":"208","author":"Huang","year":"2022","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14541","article-title":"Aryl Hydrocarbon Receptor\/Nuclear Factor E2-related Factor 2 (AHR\/NRF2) Signalling: A Novel Therapeutic Target for Atopic Dermatitis","volume":"31","author":"Hwang","year":"2022","journal-title":"Exp Dermatol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2017.05.004","article-title":"Tapinarof Is a Natural AhR Agonist That\u00a0Resolves Skin Inflammation in Mice\u00a0And\u00a0Humans","volume":"137","author":"Smith","year":"2017","journal-title":"J Invest Dermatol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2019.09.002","article-title":"Antioxidants Cinnamaldehyde and Galactomyces Fermentation Filtrate Downregulate Senescence Marker CDKN2A\/p16INK4A Via NRF2 Activation in Keratinocytes","volume":"96","author":"Hashimoto-Hachiya","year":"2019","journal-title":"J Dermatol Sci"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10112502","article-title":"Daily Fluctuation of Facial Pore Area, Roughness and Redness Among Young Japanese Women; Beneficial Effects of","volume":"10","author":"Miyamoto","year":"2021","journal-title":"J Clin Med"},{"key":"B33","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/s0031-9422(03)00142-0","article-title":"Actinidia Arguta: Volatile Compounds in Fruit and Flowers","volume":"63","author":"Matich","year":"2003","journal-title":"Phytochemistry"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2018.07.084","article-title":"Anticholinergic Effects of Actinidia Arguta Fruits and Their Polyphenol Content Determined by Liquid Chromatography-Photodiode Array Detector-Quadrupole\/Time of Flight-Mass Spectrometry (LC-MS-PDA-Q\/TOF)","volume":"271","author":"Wojdy\u0142o","year":"2019","journal-title":"Food Chem"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1042\/bj3400715","article-title":"Dietary Flavonols Quercetin and Kaempferol are Ligands of the Aryl Hydrocarbon Receptor That Affect CYP1A1 Transcription Differentially","volume":"340","author":"Ciolino","year":"1999","journal-title":"Biochem J"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1021\/tx300169e","article-title":"Quercetin, Resveratrol, and Curcumin Are Indirect Activators of the Aryl Hydrocarbon Receptor (AHR)","volume":"25","author":"Mohammadi-Bardbori","year":"2012","journal-title":"Chem Res Toxicol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14217","article-title":"Early Transcriptional Changes After UVB Treatment in Atopic Dermatitis Include Inverse Regulation of IL-36\u03b3 and IL-37","volume":"30","author":"Lossius","year":"2021","journal-title":"Exp Dermatol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2004.08.005","article-title":"Metabolic Fate of the Ah Receptor Ligand 6-Formylindolo[3,2-b]Carbazole","volume":"149","author":"Bergander","year":"2004","journal-title":"Chem Biol Interact"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2018.02.014","article-title":"Protective Role of 6-Formylindolo[3,2-b]Carbazole (FICZ), an Endogenous Ligand for Arylhydrocarbon Receptor, in Chronic Mite-Induced Dermatitis","volume":"90","author":"Kiyomatsu-Oda","year":"2018","journal-title":"J Dermatol Sci"},{"key":"B40","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.jdermsci.2019.08.006","article-title":"Interleukin-33 in Atopic Dermatitis","volume":"96","author":"Imai","year":"2019","journal-title":"J Dermatol Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130351","article-title":"A Role for IL-25 and IL-33-driven Type-2 Innate Lymphoid Cells in Atopic Dermatitis","volume":"210","author":"Salimi","year":"2013","journal-title":"J Exp Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/exd.12027","article-title":"IL-33 Is Secreted by Psoriatic Keratinocytes and Induces Pro-Inflammatory Cytokines","volume":"21","author":"Balato","year":"2012","journal-title":"Exp Dermatol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.jid.2020.07.027","article-title":"An Autocrine Circuit of IL-33 in Keratinocytes Is Involved in the Progression of Psoriasis","volume":"141","author":"Zeng","year":"2021","journal-title":"J Invest Dermatol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.696605","article-title":"Current Understanding of IL-37 in Human Health and Disease","volume":"12","author":"Su","year":"2021","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2013.04.014","article-title":"Expression of IL-33 in the Epidermis: The Mechanism of Induction by IL-17","volume":"71","author":"Meephansan","year":"2013","journal-title":"J Dermatol Sci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.534396","article-title":"Ifn-\u03b3 Directly Controls IL-33 Protein Level Through a STAT1- and LMP2-dependent Mechanism","volume":"289","author":"Kopach","year":"2014","journal-title":"J Biol Chem"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.745997\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T08:48:08Z","timestamp":1652950088000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2022.745997\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,19]]},"references-count":46,"alternative-id":["10.3389\/fimmu.2022.745997"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2022.745997","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,19]]},"article-number":"745997"}}