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Cited by 22Dermatology and Skin DiseasesPsoriasis: Treatment and PathogenesisIL-33, ST2, and ILC Pathways

Natural Compounds Tapinarof and Galactomyces Ferment Filtrate Downregulate IL-33 Expression via the AHR/IL-37 Axis in Human Keratinocytes

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Tsuji, Gaku, Hashimoto-Hachiya, Akiko, Matsuda-Taniguchi, Tomoyo, Takai-Yumine, Ayako, Takemura, Masaki, Yan, Xianghong, Furue, Masutaka, Nakahara, Takeshi·2022·Frontiers in Immunology
DOI 10.3389/fimmu.2022.745997PMC PMC9161696
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Abstract

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 Galactomyces 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 via the AHR/IL-37 axis.

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Crossref · 10.3389/fimmu.2022.745997

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  • GFF accelerates the production of the anti-inflammatory cytokine IL-37 in epidermal keratinocytes and contributes to anti-inflammaging.

    “GFF also accelerates the production of the anti-inflammatory cytokine IL-37 in epidermal keratinocytes and contributes to anti-inflammaging [9,22].”

    From Significant Reversal of Facial Wrinkle, Pigmented Spot and Roughness by Daily Application of Galactomyces Ferment Filtrate-Containing Skin Products for 12 Months—An 11-Year Longitudinal Skin Aging Rejuvenation Study (2023) · cites this paper as [22]

    The Results (page not supplied) show that GFF increased IL-37 mRNA and protein in human epidermal keratinocytes. The Discussion (page not supplied) links declining IL-37 to inflammaging but says AHR modulators such as GFF *should* be beneficial for aging; it does not demonstrate that GFF counteracts inflammaging. The Results also report intracellular IL-37 expression, not detectable secretion. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The GFF-AHR-IL-37-induced downregulation of IL-33 is canceled by knockdown of either AHR or IL-37.

    “Moreover, the GFF-AHR-IL-37-induced downregulation of IL-33 is canceled by the knockdown of either AHR or IL-37 [116].”

    From Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes (2022) · cites this paper as [116]

    The Results section ('Inhibitory Effect of Tapinarof and GFF Treatment on IL-33 Expression') reports that knockdown of either IL-37 or AHR partially reversed GFF-induced downregulation of IL-33 protein in human keratinocytes. The claim omits 'partially' and therefore overstates the extent of cancellation. Page numbers are not provided in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • GFF upregulates IL-37 expression in human keratinocytes in an AHR-dependent fashion.

    “Notably, GFF upregulated IL-37 expression in human keratinocytes in an AHR-dependent fashion [116] (Figure 2).”

    From Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes (2022) · cites this paper as [116]

  • GFF-induced IL-37 downregulates the expression of IL-33 in keratinocytes.

    “The GFF-induced IL-37 is biologically active, because it downregulates the expression of IL-33 in keratinocytes [116].”

    From Galactomyces Ferment Filtrate Potentiates an Anti-Inflammaging System in Keratinocytes (2022) · cites this paper as [116]

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Cited by

Sorted by citations

Authors
Tsuji, G., Hashimoto-Hachiya, A., Matsuda-Taniguchi, T., Takai-Yumine, A., Takemura, M., Yan, X., Furue, M., & Nakahara, T.
Affiliations
Kyushu University (JP)
Corresponding author
Tsuji, Gaku
ORCID
Venue
Frontiers in Immunology
Publisher
Frontiers Media SA
Published
2022-05-19
Volume
13
Pages
745997-745997
ISSN
1664-3224 (ISSN-L)
DOI
10.3389/fimmu.2022.745997
PMC
PMC9161696
OpenAlex
W4280531876
Cited by
22
References
3
Citations by year
2026: 3 · 2025: 1 · 2024: 9 · 2023: 7 · 2022: 2
FWCI
4.65
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Immunology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Japan Society for the Promotion of Science (20K08653)
Topics
  • Health Sciences › Medicine › Dermatology › Dermatology and Skin Diseases
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
  • Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
Keywords
tapinarof, aryl hydrocarbon receptor, IL-37, IL-33, keratinocytes, atopic dermatitis, psoriasis, natural compounds, epidermis, alarmin cytokines, keratinocyte differentiation, topical treatment
MeSH terms
Interleukin-33, Dermatitis, Atopic, Dermatologic Agents, Humans, Psoriasis, Resorcinols, Stilbenes, Keratinocytes, Receptors, Aryl Hydrocarbon

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