BMB Reports

생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
권호 표지
DOI QR코드

DOI QR Code

Anti-atopic dermatitis effects of Parasenecio auriculatus via simultaneous inhibition of multiple inflammatory pathways

  • Kwon, Yujin (Natural Product Research Center, Korea Institute of Science and Technology (KIST)) ;
  • Cho, Su-Yeon (Natural Product Research Center, Korea Institute of Science and Technology (KIST)) ;
  • Kwon, Jaeyoung (Division of Bio-Medical Science & Technology, University of Science and Technology (UST)) ;
  • Hwang, Min (Department of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Hwang, Hoseong (Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST)) ;
  • Kang, Yoon Jin (Natural Product Research Center, Korea Institute of Science and Technology (KIST)) ;
  • Lee, Hyeon-Seong (Natural Product Informatics Research Center, Korea Institute of Science and Technology (KIST)) ;
  • Kim, Jiyoon (Department of Pharmacology, Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Kim, Won Kyu (Natural Product Research Center, Korea Institute of Science and Technology (KIST))
  • 투고 : 2021.10.06
  • 심사 : 2022.01.10
  • 발행 : 2022.06.30
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

The treatment of atopic dermatitis (AD) is challenging due to its complex etiology. From epidermal disruption to chronic inflammation, various cells and inflammatory pathways contribute to the progression of AD. As with immunosuppressants, general inhibition of inflammatory pathways can be effective, but this approach is not suitable for long-term treatment due to its side effects. This study aimed to identify a plant extract (PE) with anti-inflammatory effects on multiple cell types involved in AD development and provide relevant mechanistic evidence. Degranulation was measured in RBL-2H3 cells to screen 30 PEs native to South Korea. To investigate the anti-inflammatory effects of Parasenecio auriculatus var. matsumurana Nakai extract (PAE) in AD, production of cytokines and nitric oxide, activation status of FcεRI and TLR4 signaling, cell-cell junction, and cell viability were evaluated using qRT-PCR, western blotting, confocal microscopy, Griess system, and an MTT assay in RBL-2H3, HEK293, RAW264.7, and HaCaT cells. For in vivo experiments, a DNCBinduced AD mouse model was constructed, and hematoxylin and eosin, periodic acid-Schiff, toluidine blue, and F4/80-staining were performed. The chemical constituents of PAE were analyzed by HPLC-MS. By measuring the anti-degranulation effects of 30 PEs in RBL-2H3 cells, we found that Paeonia lactiflora Pall., PA, and Rehmannia glutinosa (Gaertn.) Libosch. ex Steud. show an inhibitory activity of more than 50%. Of these, PAE most dramatically and consistently suppressed cytokine expression, including IL-4, IL-9, IL-13, and TNF-α. PAE potently inhibited FcεRI signaling, which mechanistically supports its basophil-stabilizing effects, and PAE downregulated cytokines and NO production in macrophages via perturbation of toll-like receptor signaling. Moreover, PAE suppressed cytokine production in keratinocytes and upregulated the expression of tight junction molecules ZO-1 and occludin. In a DNCB-induced AD mouse model, the topical application of PAE significantly improved atopic index scores, immune cell infiltration, cytokine expression, abnormal activation of signaling molecules in FcεRI and TLR signaling, and damaged skin structure compared with dexamethasone. The anti-inflammatory effect of PAE was mainly due to integerrimine. Our findings suggest that PAE could potently inhibit multi-inflammatory cells involved in AD development, synergistically block the propagation of inflammatory responses, and thus alleviate AD symptoms.

키워드

과제정보

This work was supported by funding from the Catholic Medical Center Research Foundation made in the program year of 2020 (to J.K.) and the Korea Institute of Science & Technology Research Program (2E31300).

참고문헌

  1. Weidinger S and Novak N (2016) Atopic dermatitis. Lancet 387, 1109-1122 https://doi.org/10.1016/S0140-6736(15)00149-X
  2. Silverberg JI (2019) Comorbidities and the impact of atopic dermatitis. Ann Allergy Asthma Immunol 123, 144-151 https://doi.org/10.1016/j.anai.2019.04.020
  3. Mack MR and Kim BS (2018) The itch-scratch cycle: a neuroimmune perspective. Trends Immunol 39, 980-991 https://doi.org/10.1016/j.it.2018.10.001
  4. Brunello L (2018) Atopic dermatitis. Nat Rev Dis Primers 4, 2 https://doi.org/10.1038/s41572-018-0004-9
  5. Boguniewicz M and Leung DY (2011) Atopic dermatitis: a disease of altered skin barrier and immune dysregulation. Immunol Rev 242, 233-246 https://doi.org/10.1111/j.1600-065X.2011.01027.x
  6. Yamanishi Y, Mogi K, Takahashi K, Miyake K, Yoshikawa S and Karasuyama H (2020) Skin-infiltrating basophils promote atopic dermatitis-like inflammation via IL-4 production in mice. Allergy 75, 2613-2622 https://doi.org/10.1111/all.14362
  7. Vestergaard C, Wollenberg A and Thyssen JP (2020) European Task Force on Atopic Dermatitis (ETFAD) Position Paper: treatment of parental atopic dermatitis during preconception, pregnancy and lactation period. J Eur Acad Dermatol Venereol 34, 426-427 https://doi.org/10.1111/jdv.16171
  8. Thyssen JP, Vestergaard C, Deleuran M et al (2020) European Task Force on Atopic Dermatitis (ETFAD): treatment targets and treatable traits in atopic dermatitis. J Eur Acad Dermatol Venereol 34, e839-e842 https://doi.org/10.1111/jdv.16716
  9. Wu J and Guttman-Yassky E (2020) Efficacy of biologics in atopic dermatitis. Expert Opin Biol Ther 20, 525-538 https://doi.org/10.1080/14712598.2020.1722998
  10. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M and O'Shea JJ (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 17, 78
  11. Eichenfield LF, Ahluwalia J, Waldman A, Borok J, Udkoff J and Boguniewicz M (2017) Current guidelines for the evaluation and management of atopic dermatitis: a comparison of the Joint Task Force Practice Parameter and American Academy of Dermatology guidelines. J Allergy Clin Immunol 139, S49-S57 https://doi.org/10.1016/j.jaci.2017.01.009
  12. Strehl C, Ehlers L, Gaber T and Buttgereit F (2019) Glucocorticoids-all-rounders tackling the versatile players of the immune system. Front Immunol 10, 1744 https://doi.org/10.3389/fimmu.2019.01744
  13. Akinlade B, Guttman-Yassky E, de Bruin-Weller M et al (2019) Conjunctivitis in dupilumab clinical trials. Br J Dermatol 181, 459-473 https://doi.org/10.1111/bjd.17869
  14. Mechesso AF, Lee SJ, Park NH et al (2019) Preventive effects of a novel herbal mixture on atopic dermatitis-like skin lesions in BALB/C mice. BMC Complement Altern Med 19, 25 https://doi.org/10.1186/s12906-018-2426-z
  15. Yun Y, Kim K, Choi I and Ko SG (2014) Topical herbal application in the management of atopic dermatitis: a review of animal studies. Mediators Inflamm 2014, 752103 https://doi.org/10.1155/2014/752103
  16. Kim JH, Kim YH and Yoon CY (2010) Vascular plants of the Hongcheon-gun area in Gangwon province - Mt. Gyebang, Mt. Gongjak, Mt. Daeryong, Mt. Maehwa, Mt. Eungbong, and Chimseok peak. Korean J Environ Ecol 24, 32
  17. Weidinger S, Beck LA, Bieber T, Kabashima K and Irvine AD (2018) Atopic dermatitis. Nat Rev Dis Primers 4, 1
  18. Bieber T (2022) Atopic dermatitis: an expanding therapeutic pipeline for a complex disease. Nat Rev Drug Discov 21, 21-40 https://doi.org/10.1038/s41573-021-00266-6
  19. MacGlashan D Jr (2008) IgE receptor and signal transduction in mast cells and basophils. Curr Opin Immunol 20, 717-723 https://doi.org/10.1016/j.coi.2008.08.004
  20. Bhaskar S and Helen A (2016) Quercetin modulates toll-like receptor-mediated protein kinase signaling pathways in oxLDL-challenged human PBMCs and regulates TLR-activated atherosclerotic inflammation in hypercholesterolemic rats. Mol Cell Biochem 423, 53-65 https://doi.org/10.1007/s11010-016-2824-9
  21. Ko E, Park S, Lee JH et al (2019) Ginsenoside Rh2 ameliorates atopic dermatitis in NC/Nga mice by suppressing NF-kappaB-mediated thymic stromal lymphopoietin expression and T helper type 2 differentiation. Int J Mol Sci 20, 6111 https://doi.org/10.3390/ijms20246111
  22. Choi YJ, Lee HJ, Lee DH et al (2013) Therapeutic effects and immunomodulation of suanbo mineral water therapy in a murine model of atopic dermatitis. Ann Dermatol 25, 462-470 https://doi.org/10.5021/ad.2013.25.4.462
  23. Kasraie S and Werfel T (2013) Role of macrophages in the pathogenesis of atopic dermatitis. Mediators Inflamm 2013, 942375
  24. Bao K and Reinhardt RL (2015) The differential expression of IL-4 and IL-13 and its impact on type-2 immunity. Cytokine 75, 25-37 https://doi.org/10.1016/j.cyto.2015.05.008
  25. Junttila IS (2018) Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front Immunol 9, 888 https://doi.org/10.3389/fimmu.2018.00888
  26. Lin SH, Chuang HY, Ho JC, Lee CH and Hsiao CC (2018) Treatment with TNF-alpha inhibitor rectifies M1 macrophage polarization from blood CD14+ monocytes in patients with psoriasis independent of STAT1 and IRF-1 activation. J Dermatol Sci 91, 276-284 https://doi.org/10.1016/j.jdermsci.2018.05.009
  27. Toma W, Trigo JR, de Paula AC and Brito AR (2004) Preventive activity of pyrrolizidine alkaloids from Seneciobrasiliensis (Asteraceae) on gastric and duodenal induced ulcer on mice and rats. J Ethnopharmacol 95, 345-351 https://doi.org/10.1016/j.jep.2004.08.017