Highlights
- •FICZ upregulated the expression of filaggrin in keratinocytes via AHR.
- •In dermatitis-affected mouse skin, the expression of filaggrin was recovered by FICZ.
- •FICZ improved mite-induced chronic dermatitis and TEWL in NC/Nga mice.
Abstract
Background
Chronic eczema such as atopic dermatitis imposes significant socio-econo-psychologic
burdens on the affected individuals. In addition to conventional topical treatments,
phototherapy is recommended for patients with extensive lesions. Although immunosuppression
is believed to explain its primary effectiveness, the underlying mechanisms of phototherapy
remain unsolved. Ultraviolet irradiation generates various tryptophan photoproducts
including 6-formylindolo[3,2-b]-carbazole (FICZ). FICZ is known to be a potent endogenous
agonist for aryl hydrocarbon receptor (AHR); however, the biological role of FICZ
in chronic eczema is unknown.
Objective
To investigate the effect of FICZ on chronic eczema such as atopic dermatitis.
Methods
We stimulated HaCaT cells and normal human epidermal keratinocytes (NHEKs) with or
without FICZ and then performed quantitative reverse transcriptase polymerase chain
reaction, immunofluorescence, and siRNA treatment. We used the atopic dermatitis-like
NC/Nga murine model and treated the mice for 2 weeks with either Vaseline® as a control, FICZ ointment, or betamethasone 17-valerate ointment. The dermatitis
score, transepidermal water loss, histology, and expression of skin barrier genes
and proteins were evaluated.
Results
FICZ significantly upregulated the gene expression of filaggrin in both HaCaT cells
and NHEKs in an AHR-dependent manner, but did not affect the gene expression of other
barrier-related proteins. In addition, FICZ improved the atopic dermatitis-like skin
inflammation, clinical scores, and transepidermal water loss in NC/Nga mice compared
with those of control mice. On histology, FICZ significantly reduced the epidermal
and dermal thickness as well as the number of mast cells. Topical FICZ also significantly
reduced the gene expression of Il22.
Conclusion
These findings highlight the beneficial role of FICZ-AHR and provide a new strategic
basis for developing new drugs for chronic eczema.
Abbreviations:
FICZ (6-formylindolo[3,2-b]-carbazole), AHR (aryl hydrocarbon receptor), NHEKs (normal human epidermal keratinocytes), TEWL (transepidermal water loss), FLG (filaggrin), UV (ultraviolet)Keywords
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References
- Functional role of AhR in the expression of toxic effects by TCDD.Biochim. Biophys. Acta. 1619; 2003: 263-268
- The emerging roles of AhR in physiology and immunity.Biochem. Pharmacol. 2013; 86: 561-570
- Role of AhR/ARNT system in skin homeostasis.Arch. Dermatol. Res. 2014; 306: 769-779
- Gene regulation of filaggrin and other skin barrier proteins via aryl hydrocarbon receptor.J. Dermatol. Sci. 2015; 80: 83-88
- The aryl hydrocarbon receptor: multitasking in the immune system.Annu. Rev. Immunol. 2014; 32: 403-432
- Activation of the aryl hydrocarbon receptor dampens the severity of inflammatory skin conditions.Immunity. 2014; 40: 989-1001
- Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation.Proc. Natl. Acad. Sci. U. S. A. 2007; 104: 8851-8856
- The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans.J. Biol. Chem. 2009; 284: 2690-2696
- Indole and tryptophan metabolism: endogenous and dietary routes to ah receptor activation.Drug Metab. Dispos. 2015; 43: 1522-1535
- A novel atopic dermatitis model induced by topical application with dermatophagoides farinae extract in NC/Nga mice.Allergol. Int. 2007; 56: 139-148
- Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis.J. Clin. Invest. 2013; 123: 917-927
- Antioxidant soybean tar Glyteer rescues T-helper-mediated downregulation of filaggrin expression via aryl hydrocarbon receptor.J. Dermatol. 2015; 42: 171-180
- Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis.Nat. Genet. 2006; 38: 441-446
- Multifactorial skin barrier deficiency and atopic dermatitis: essential topics to prevent the atopic march.J. Allergy Clin. Immunol. 2016; 138: 350-358
- Altered stratum corneum barrier and enhanced percutaneous immune responses in filaggrin-null mice.J. Allergy Clin. Immunol. 2012; 129: 1538-1546
- Spontaneous atopic dermatitis is mediated by innate immunity: with the secondary lung inflammation of the atopic march requiring adaptive immunity.J. Allergy Clin. Immunol. 2016; 137: 482-491
- Topical apigenin improves epidermal permeability barrier homoeostasis in normal murine skin by divergent mechanisms.Exp. Dermatol. 2013; 22: 210-215
- Therapeutic approach to mite-induced intractable dermatitis using novel immunomodulator FTY720 ointment (fingolimod) in NC/Nga mice.Allergol. Int. 2016; 65: 172-179
- An environmental contaminant benzo(a)pyrene, induces oxidative stress-mediated interleukin-8 production in human keratinocytes via the aryl hydrocarbon receptor signaling pathway.J. Dermatol. Sci. 2011; 62: 42-49
- Role of the arylhydrocarbon receptor (AhR) in the pathology of asthma and COPD.J. Allergy (Cairo). 2012; 2012: 372384
- Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles.Science. 2011; 334: 1561-1565
- Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation.Cell. 2011; 147: 629-640
- Aryl hydrocarbon receptor in keratinocytes is essential for murine skin barrier integrity.J. Invest. Dermatol. 2016; 136: 2260-2269
- Antioxidants for healthy skin: the emerging role of aryl hydrocarbon receptors and nuclear factor-erythroid 2-related factor-2.Nutrients. 2017; 9: 223
- AHR function in lymphocytes: emerging concepts.Trends Immunol. 2016; 37: 17-31
- Feedback control of AHR signalling regulates intestinal immunity.Nature. 2017; 542: 242-245
- 2,3,7,8-Tetrachlorodibenzo-p-dioxin increases the expression of genes in the human epidermal differentiation complex and accelerates epidermal barrier formation.Toxicol. Sci. 2011; 124: 128-137
- 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated production of reactive oxygen species is an essential step in the mechanism of action to accelerate human keratinocyte differentiation.Toxicol. Sci. 2013; 132: 235-249
- The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the ‘fused genes' family.Exp. Dermatol. 2012; 21: 643-649
- Metabolic fate of the Ah receptor ligand 6-formylindolo[3,2-b]carbazole.Chem. Biol. Interact. 2004; 149: 151-164
- Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract.Gastroenterology. 2011; 141: 237-248
- FICZ, a tryptophan photoproduct, suppresses pulmonary eosinophilia and Th2-type cytokine production in a mouse model of ovalbumin-induced allergic asthma.Int. Immunopharmacol. 2012; 13: 377-385
- FcεRI stimulation promotes the differentiation of histamine receptor 1-expressing inflammatory macrophages.Allergy. 2013; 68: 454-461
- Filaggrin mutations increase the risk for persistent dry skin and eczema independent of sensitization.J. Allergy Clin. Immunol. 2012; 129: 1153-1155
- Early pediatric atopic dermatitis shows only a cutaneous lymphocyte antigen (CLA)(+) TH2/TH1 cell imbalance, whereas adults acquire CLA(+) TH22/TC22 cell subsets.J. Allergy Clin. Immunol. 2015; 136: 941-951
- Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin.J. Allergy Clin. Immunol. 2016; 138: 1639-1651
- Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis.Clin. Immunol. 2018; https://doi.org/10.1016/j.jaci.2017.01.027
- Expression of IL-22 in the skin causes Th2-biased Immunity epidermal barrier dysfunction, and pruritus via stimulating epithelial Th2 cytokines and the GRP pathway.J. Immunol. 2017; 198: 2543-2555
- Interleukin-22 downregulates filaggrin expression and affects expression of profilaggrin processing enzymes.Br. J. Dermatol. 2011; 165: 492-498
- IL-22-producing T22 T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17-producing TH17 T cells.J. Allergy Clin. Immunol. 2009; 123: 1244-1252
- Aryl hydrocarbon receptor promotes RORγt+ group 3 ILCs and controls intestinal immunity and inflammation.Semin. Immunopathol. 2013; 35: 657-670
- Differential influences of the aryl hydrocarbon receptor on Th17 mediated responses in vitro and in vivo.PLoS One. 2013; 8: e79819
- ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients.J. Eur. Acad. Dermatol. Venereol. 2016; 30: 729-747
- Clinical practice guidelines for the management of atopic dermatitis 2016.J. Dermatol. 2016; 43: 1117-1145
- Systematic review of UV-based therapy for psoriasis.Am. J. Clin. Dermatol. 2013; 14: 87-109
- The dark and the sunny sides of UVR-induced immunosuppression: photoimmunology revisited.J. Invest. Dermatol. 2010; 130: 49-54
- The Aryl hydrocarbon receptor is involved in UVR-induced immunosuppression.J. Invest. Dermatol. 2013; 133: 2763-2770
- Biopositive effects of low-dose UVB on epidermis: coordinate upregulation of antimicrobial peptides and permeability barrier reinforcement.J. Invest. Dermatol. 2008; 128: 2880-2887
Article info
Publication history
Published online: February 21, 2018
Accepted:
February 19,
2018
Received in revised form:
February 13,
2018
Received:
July 6,
2017
Identification
Copyright
© 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
