Osthole Inhibits Expression of Genes Associated with Toll-like Receptor 2 Signaling Pathway in an Organotypic 3D Skin Model of Human Epidermis with Atopic Dermatitis

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Jan 11

PMID 35011650

Authors

Natalia Karolina Kordulewska

Justyna Topa

Robert Stryinski

Beata Jarmolowska

Affiliations

Soon will be listed here.

Abstract

The Toll-like receptor (TLR) family signature has been linked to the etiopathology of atopic dermatitis (AD), a chronic inflammatory skin disease associated with skin barrier dysfunction and immune system imbalance. We aimed to investigate whether osthole (a plant-derived compound) can inhibit the genetic profile of key genes associated with TLR2 signaling (, , , , , ) after stimulation with LPS or histamine in a 3D in vitro model of AD. Overexpression of the aforementioned genes may directly increase the secretion of proinflammatory cytokines (CKs) and chemokines (ChKs), which may exacerbate the symptoms of AD. Relative gene expressions were quantified by qPCR and secretion of CKs and ChKs was evaluated by ELISA assay. LPS and histamine increased the relative expression of genes related to the TLR2 pathway, and osthole successfully reduced it. In summary, our results show that osthole inhibits the expression of genes associated with the TLR signaling pathway in a skin model of AD. Moreover, the secretion of CKs and ChKs after treatment of AD with osthole in a 3D skin model in vitro suggests the potential of osthole as a novel compound for the treatment of AD.

Citing Articles

Toll-like receptors in atopic dermatitis: pathogenesis and therapeutic implications.

Vafaeian A, Rajabi F, Rezaei N Heliyon. 2025; 11(3):e42226.

PMID: 40007792 PMC: 11850170. DOI: 10.1016/j.heliyon.2025.e42226.

Protective and Anti-Inflammatory Effect of Novel Formulation Based on High and Low Molecular Weight Hyaluronic Acid and .

DAgostino M, Giori A, Vassallo V, Schiraldi C, DAgostino A Int J Mol Sci. 2025; 26(3).

PMID: 39941078 PMC: 11818062. DOI: 10.3390/ijms26031310.

The Effect of Osthole on Transient Receptor Potential Channels: A Possible Alternative Therapy for Atopic Dermatitis.

Kordulewska N, Krol-Grzymala A J Inflamm Res. 2024; 17:881-898.

PMID: 38351985 PMC: 10863468. DOI: 10.2147/JIR.S425978.

Larva Trypsin Hydrolysate Ameliorates Atopic Dermatitis in C57BL/6 Mice by Targeting the TLR-Mediated MyD88-Dependent MAPK Signaling Pathway.

Fan M, Wedamulla N, Choi Y, Zhang Q, Bae S, Kim E Nutrients. 2023; 15(1).

PMID: 36615751 PMC: 9824148. DOI: 10.3390/nu15010093.

models for investigating itch.

Miessner H, Seidel J, Smith E Front Mol Neurosci. 2022; 15:984126.

PMID: 36385768 PMC: 9644192. DOI: 10.3389/fnmol.2022.984126.

References

Yu Y, Zhang Y, Zhang J, Dou X, Yang H, Shao Y . Impaired Toll-like receptor 2-mediated Th1 and Th17/22 cytokines secretion in human peripheral blood mononuclear cells from patients with atopic dermatitis. J Transl Med. 2015; 13:384. PMC: 4683963. DOI: 10.1186/s12967-015-0744-1. View

Niebuhr M, Lutat C, Sigel S, Werfel T . Impaired TLR-2 expression and TLR-2-mediated cytokine secretion in macrophages from patients with atopic dermatitis. Allergy. 2009; 64(11):1580-7. DOI: 10.1111/j.1398-9995.2009.02050.x. View

Anwar M, Basith S, Choi S . Negative regulatory approaches to the attenuation of Toll-like receptor signaling. Exp Mol Med. 2013; 45:e11. PMC: 3584666. DOI: 10.1038/emm.2013.28. View

Jiao D, Wong C, Qiu H, Dong J, Cai Z, Chu M . NOD2 and TLR2 ligands trigger the activation of basophils and eosinophils by interacting with dermal fibroblasts in atopic dermatitis-like skin inflammation. Cell Mol Immunol. 2015; 13(4):535-50. PMC: 4947824. DOI: 10.1038/cmi.2015.77. View

Kordulewska N, Cieslinska A, Fiedorowicz E, Jarmolowska B, Kostyra E . High Expression of IL-1RI and EP₂ Receptors in the IL-1β/COX-2 Pathway, and a New Alternative to Non-Steroidal Drugs-Osthole in Inhibition COX-2. Int J Mol Sci. 2019; 20(1). PMC: 6337662. DOI: 10.3390/ijms20010186. View

Yoo J, Omori M, Gyarmati D, Zhou B, Aye T, Brewer A . Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J Exp Med. 2005; 202(4):541-9. PMC: 2212851. DOI: 10.1084/jem.20041503. View

Sun L, Liu W, Zhang L . The Role of Toll-Like Receptors in Skin Host Defense, Psoriasis, and Atopic Dermatitis. J Immunol Res. 2019; 2019:1824624. PMC: 6877906. DOI: 10.1155/2019/1824624. View

Lai Y, Dong C . Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases. Int Immunol. 2015; 28(4):181-8. PMC: 4889878. DOI: 10.1093/intimm/dxv063. View

Han H, Roan F, Ziegler S . The atopic march: current insights into skin barrier dysfunction and epithelial cell-derived cytokines. Immunol Rev. 2017; 278(1):116-130. PMC: 5492959. DOI: 10.1111/imr.12546. View

10.

Tang D, Hou W, Zhou Q, Zhang M, Holz J, Sheu T . Osthole stimulates osteoblast differentiation and bone formation by activation of beta-catenin-BMP signaling. J Bone Miner Res. 2010; 25(6):1234-45. PMC: 3153131. DOI: 10.1002/jbmr.21. View

11.

Jin H, Kumar L, Mathias C, Zurakowski D, Oettgen H, Gorelik L . Toll-like receptor 2 is important for the T(H)1 response to cutaneous sensitization. J Allergy Clin Immunol. 2009; 123(4):875-82.e1. PMC: 2685075. DOI: 10.1016/j.jaci.2009.02.007. View

12.

Kim C, Park K, Ahn S, Kim D, Li K, Kim D . Economic Impact of Atopic Dermatitis in Korean Patients. Ann Dermatol. 2015; 27(3):298-305. PMC: 4466283. DOI: 10.5021/ad.2015.27.3.298. View

13.

Kaminska B . MAPK signalling pathways as molecular targets for anti-inflammatory therapy--from molecular mechanisms to therapeutic benefits. Biochim Biophys Acta. 2005; 1754(1-2):253-62. DOI: 10.1016/j.bbapap.2005.08.017. View

14.

Tyurin Y, Shamsutdinov A, Kalinin N, Sharifullina A, Reshetnikova I . Association of Toll-Like Cell Receptors TLR2 (p.Arg753GLN) and TLR4 (p.Asp299GLY) Polymorphisms with Indicators of General and Local Immunity in Patients with Atopic Dermatitis. J Immunol Res. 2017; 2017:8493545. PMC: 5448057. DOI: 10.1155/2017/8493545. View

15.

Huang G, Bhaskar Reddy M, Kuo P, Huang C, Shih H, Lee E . A concise synthesis of viscolin, and its anti-inflammatory effects through the suppression of iNOS, COX-2, ERK phosphorylation and proinflammatory cytokines expressions. Eur J Med Chem. 2011; 48:371-8. DOI: 10.1016/j.ejmech.2011.12.008. View

16.

Ollmar S, Eek A, Sundstrom F, Emtestam L . Electrical impedance for estimation of irritation in oral mucosa and skin. Med Prog Technol. 1995; 21(1):29-37. View

17.

Yang S, Chan Y, Hua K, Chang J, Chen H, Tsai Y . Osthole improves an accelerated focal segmental glomerulosclerosis model in the early stage by activating the Nrf2 antioxidant pathway and subsequently inhibiting NF-κB-mediated COX-2 expression and apoptosis. Free Radic Biol Med. 2014; 73:260-9. DOI: 10.1016/j.freeradbiomed.2014.05.009. View

18.

Cai Y, Sun W, Zhang X, Lin Y, Chen H, Li H . Osthole prevents acetaminophen-induced liver injury in mice. Acta Pharmacol Sin. 2017; 39(1):74-84. PMC: 5758662. DOI: 10.1038/aps.2017.129. View

19.

Wee J, Zhang Y, Rhee C, Kim D . Inhibition of Allergic Response by Intranasal Selective NF-κB Decoy Oligodeoxynucleotides in a Murine Model of Allergic Rhinitis. Allergy Asthma Immunol Res. 2016; 9(1):61-69. PMC: 5102837. DOI: 10.4168/aair.2017.9.1.61. View

20.

Gohda J, Matsumura T, Inoue J . Cutting edge: TNFR-associated factor (TRAF) 6 is essential for MyD88-dependent pathway but not toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta (TRIF)-dependent pathway in TLR signaling. J Immunol. 2004; 173(5):2913-7. DOI: 10.4049/jimmunol.173.5.2913. View