Skip to main content

Advertisement

SpringerLink
Log in

Igalan from Inula helenium (L.) suppresses the atopic dermatitis-like response in stimulated HaCaT keratinocytes via JAK/STAT3 signaling

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

This study aimed to evaluate the protective effect of igalan, a sesquiterpene lactone isolated from Inula helenium (L.), on inhibiting inflammation, regulating the epidermal differentiation gene expression, and reactive oxygen species scavenging in atopic dermatitis (AD)-like inflammatory keratinocytes.

Methods

HaCaT human keratinocytes were treated with igalan at indicated concentrations before being activated by a combination of TNF-α and IFN-γ or IL-4 representative for T-helper 1 and T-helper 2 cell cytokines, which are associated with AD pathogenesis.

Results

By inhibiting the NF-κB pathway as well as the STAT activation, igalan could downregulate several marker inflammatory genes in AD, such as TARC/CCL17, MDC/CCL22, and RANTES/CCL5. In contrast, igalan, acting as JAK inhibitor, could promote the mRNA expression levels of the genes FLG, LOR, KRT10, and DSC1, which encode for essential proteins responsible for keratinocyte differentiation, by inhibiting STAT3 signaling. Furthermore, igalan exerts its antioxidant effect through activating the Nrf2 pathway, triggering the expression of some enzymes that contribute to preventing intracellular ROS generation during inflammation.

Conclusion

These findings indicate that igalan, via suppressing JAK/STAT3 signaling, could impair the production of pro-inflammatory chemokines and enhance expression levels of several genes involved in keratinocyte differentiation in AD-like stimulated keratinocytes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Dainichi T, Hanakawa S, Kabashima K. Classification of inflammatory skin diseases: a proposal based on the disorders of the three-layered defense systems, barrier, innate immunity and acquired immunity. J Dermatol Sci. 2014;76(2):81–9. https://doi.org/10.1016/j.jdermsci.2014.08.010.

    Article  PubMed  Google Scholar 

  2. Furue M, Chiba T, Tsuji G, Ulzii D, Kido-Nakahara M, Nakahara T, Kadono T. Atopic dermatitis: immune deviation, barrier dysfunction, IgE autoreactivity and new therapies. Allergol Int. 2017;66(3):398–403. https://doi.org/10.1016/j.alit.2016.12.002.

    Article  PubMed  CAS  Google Scholar 

  3. Wong ITY, Tsuyuki RT, Cresswell-Melville A, Doiron P, Drucker AM. Guidelines for the management of atopic dermatitis (eczema) for pharmacists. Can Pharm J (Ott). 2017;150(5):285–97. https://doi.org/10.1177/1715163517710958.

    Article  PubMed Central  Google Scholar 

  4. Murota H, Takeuchi S, Sugaya M, Tanioka M, Onozuka D, Hagihara A, Saeki H, Imafuku S, Abe M, Shintani Y, Kaneko S, Masuda K, Hiragun T, Inomata N, Kitami Y, Tsunemi Y, Abe S, Kobayashi M, Morisky DE, Furue M, Katoh N. Characterization of socioeconomic status of Japanese patients with atopic dermatitis showing poor medical adherence and reasons for drug discontinuation. J Dermatol Sci. 2015;79(3):279–87. https://doi.org/10.1016/j.jdermsci.2015.05.010.

    Article  PubMed  Google Scholar 

  5. Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of topical glucocorticosteroids. J Am Acad Dermatol. 2006;54(1):1–15. https://doi.org/10.1016/j.jaad.2005.01.010.

    Article  PubMed  Google Scholar 

  6. Saaf AM, Tengvall-Linder M, Chang HY, Adler AS, Wahlgren CF, Scheynius A, Nordenskjold M, Bradley M. Global expression profiling in atopic eczema reveals reciprocal expression of inflammatory and lipid genes. PLoS ONE ONE. 2008. https://doi.org/10.1371/journal.pone.0004017.

    Article  Google Scholar 

  7. Giridharan S, Srinivasan M. Mechanisms of NF-kappaB p65 and strategies for therapeutic manipulation. J Inflamm Res. 2018;11:407–19. https://doi.org/10.2147/JIR.S140188.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT. 2013. https://doi.org/10.4161/jkst.24137.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Klonowska J, Gleń J, Nowicki RJ, Trzeciak M. New cytokines in the pathogenesis of atopic dermatitis—new therapeutic targets. Int J Mol Sci. 2018;19:3086.

    Article  CAS  Google Scholar 

  10. Omata N, Tsukahara H, Ito S, Ohshima Y, Yasutomi M, Yamada A, Jiang M, Hiraoka M, Nambu M, Deguchi Y, Mayumi M. Increased oxidative stress in childhood atopic dermatitis. Life Sci. 2001;69(2):223–8.

    Article  CAS  Google Scholar 

  11. Nakai K, Yoneda K, Maeda R, Munehiro A, Fujita N, Yokoi I, Moriue J, Moriue T, Kosaka H, Kubota Y. Urinary biomarker of oxidative stress in patients with psoriasis vulgaris and atopic dermatitis. J Eur Acad Dermatol Venereol. 2009;23(12):1405–8.

    Article  CAS  Google Scholar 

  12. Lee KM, Shin JM, Chun J, Song K, Nho CW, Kim YS. Igalan induces detoxifying enzymes mediated by the Nrf2 pathway in HepG2 cells. J Biochem Mol Toxicol. 2019. https://doi.org/10.1002/jbt.22297.

    Article  PubMed  Google Scholar 

  13. Moon KY, Hahn BS, Lee J, Kim YS. A cell-based assay system for monitoring NF-kappaB activity in human HaCat transfectant cells. Anal Biochem. 2001;292(1):17–211. https://doi.org/10.1006/abio.2001.5059.

    Article  PubMed  CAS  Google Scholar 

  14. Chun J, Choi RJ, Khan S, Lee DS, Kim YC, Nam YJ, Lee DU, Kim YS. Alantolactone suppresses inducible nitric oxide synthase and cyclooxygenase-2 expression by down-regulating NF-kappaB, MAPK and AP-1 via the MyD88 signaling pathway in LPS-activated RAW 264.7 cells. Int Immunopharmacol. 2012;14(4):375–83. https://doi.org/10.1016/j.intimp.2012.08.011.

    Article  PubMed  CAS  Google Scholar 

  15. O'Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity. 2012;36(4):542–50. https://doi.org/10.1016/j.immuni.2012.03.014.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Jeong SJ, Lim HS, Seo CS, Jin SE, Yoo SR, Lee N, Shin HK. Anti-inflammatory actions of herbal formula Gyejibokryeong-hwan regulated by inhibiting chemokine production and STAT1 activation in HaCaT cells. Biol Pharm Bull. 2015;38(3):425–34. https://doi.org/10.1248/bpb.b14-00660.

    Article  PubMed  CAS  Google Scholar 

  17. Horiuchi Y, Bae SJ, Katayama I. Overexpression of the suppressor of cytokine signalling 3 (SOCS3) in severe atopic dermatitis. Clin Exp Dermatol. 2006;31(1):100–4. https://doi.org/10.1111/j.1365-2230.2005.01979.x.

    Article  PubMed  CAS  Google Scholar 

  18. David M, Ford D, Bertoglio J, Maizel AL, Pierre J. Induction of the IL-13 receptor alpha2-chain by IL-4 and IL-13 in human keratinocytes: involvement of STAT6, ERK and p38 MAPK pathways. Oncogene. 2001;20(46):6660–8. https://doi.org/10.1038/sj.onc.1204629.

    Article  PubMed  CAS  Google Scholar 

  19. Sun Y, Lu Q, He L, Shu Y, Zhang S, Tan S, Tang L. Active fragment of Veronica ciliata Fisch. attenuates t-BHP-induced oxidative stress injury in HepG2 cells through antioxidant and antiapoptosis activities. Oxid Med Cell Longev. 2017. https://doi.org/10.1155/2017/4727151.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Morgan MJ, Liu Z-g. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res. 2010;21:103. https://doi.org/10.1038/cr.2010.178.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Leung DYM, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Investig. 2004;113(5):651–7. https://doi.org/10.1172/JCI21060.

    Article  PubMed  CAS  Google Scholar 

  22. Danso MO, van Drongelen V, Mulder A, van Esch J, Scott H, van Smeden J, El Ghalbzouri A, Bouwstra JA. TNF-α and Th2 cytokines induce atopic dermatitis-like features on epidermal differentiation proteins and stratum corneum lipids in human skin equivalents. J Investig Dermatol. 2014;134(7):1941–50. https://doi.org/10.1038/jid.2014.83.

    Article  PubMed  CAS  Google Scholar 

  23. De Vuyst E, Salmon M, Evrard C, de Rouvroit CL, Poumay Y. Atopic dermatitis studies through in vitro models. Front Med. 2017. https://doi.org/10.3389/fmed.2017.00119.

    Article  Google Scholar 

  24. Lim HS, Yo SR, Lee MY, Seo CS, Shin HK, Jeong SJ. Potential inhibitory effects of the traditional herbal prescription Hyangso-san against skin inflammation via inhibition of chemokine production and inactivation of STAT1 in HaCaT keratinocytes. Mol Med Rep. 2018;17(2):2515–22. https://doi.org/10.3892/mmr.2017.8172.

    Article  PubMed  CAS  Google Scholar 

  25. Gluck J, Rogala B. Chemokine RANTES in atopic dermatitis. Arch Immunol Ther Exp (Warsz). 1999;47(6):367–72.

    PubMed  CAS  Google Scholar 

  26. Shimada Y, Takehara K, Sato S. Both Th2 and Th1 chemokines (TARC/CCL17, MDC/CCL22, and Mig/CXCL9) are elevated in sera from patients with atopic dermatitis. J Dermatol Sci. 2004;34(3):201–8. https://doi.org/10.1016/j.jdermsci.2004.01.001.

    Article  PubMed  CAS  Google Scholar 

  27. Thijs JL, de Bruin-Weller MS, Hijnen D. Current and future biomarkers in atopic dermatitis. Immunol Allergy Clin North Am. 2017;37(1):51–61. https://doi.org/10.1016/j.iac.2016.08.008.

    Article  PubMed  Google Scholar 

  28. Leyva-Castillo JM, Hener P, Jiang H, Li M. TSLP produced by keratinocytes promotes allergen sensitization through skin and thereby triggers atopic march in mice. J Invest Dermatol. 2013;133(1):154–63. https://doi.org/10.1038/jid.2012.239.

    Article  PubMed  CAS  Google Scholar 

  29. Seki Y, Inoue H, Nagata N, Hayashi K, Fukuyama S, Matsumoto K, Komine O, Hamano S, Himeno K, Inagaki-Ohara K, Cacalano N, O'Garra A, Oshida T, Saito H, Johnston JA, Yoshimura A, Kubo M. SOCS-3 regulates onset and maintenance of T(H)2-mediated allergic responses. Nat Med. 2003;9(8):1047–54. https://doi.org/10.1038/nm896.

    Article  PubMed  Google Scholar 

  30. Goren I, Linke A, Muller E, Pfeilschifter J, Frank S. The suppressor of cytokine signaling-3 is upregulated in impaired skin repair: implications for keratinocyte proliferation. J Invest Dermatol. 2006;126(2):477–85. https://doi.org/10.1038/sj.jid.5700063.

    Article  PubMed  CAS  Google Scholar 

  31. Candi E, Schmidt R, Melino G. The cornified envelope: a model of cell death in the skin. Nat Rev Mol Cell Biol. 2005;6(4):328–40. https://doi.org/10.1038/nrm1619.

    Article  PubMed  CAS  Google Scholar 

  32. Omori-Miyake M, Yamashita M, Tsunemi Y, Kawashima M, Yagi J. In vitro assessment of IL-4- or IL-13-mediated changes in the structural components of keratinocytes in mice and humans. J Invest Dermatol. 2014;134(5):1342–50. https://doi.org/10.1038/jid.2013.503.

    Article  PubMed  CAS  Google Scholar 

  33. Wang Q, Gao S, Wu G-Z, Yang N, Zu X-P, Li W-C, Xie N, Zhang R-R, Li C-W, Hu Z-L, Zhang W-D. Total sesquiterpene lactones isolated from Inula helenium L. attenuates 2,4-dinitrochlorobenzene-induced atopic dermatitis-like skin lesions in mice. Phytomedicine. 2018;46:78–84. https://doi.org/10.1016/j.phymed.2018.04.036.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grants (NRF-2017R1A2B4009301) from the National Research Foundation of Korea and Korea Institute of Science and Technology (KIST370C-20190043). We appreciate the technical support from Ms. Ji Yoon Lee, the College of Pharmacy, Seoul National University.

Author information

Authors and Affiliations

  1. College of Pharmacy and Natural Product Research Institute, Seoul National University, 1 Gwanak-ro 1, Gwanak-gu, Seoul, 08826, South Korea

    Thien T. P. Dao, Kwangho Song, Jee Young Kim & Yeong Shik Kim

  2. CHD Medics Co, Goyang-si, Gyeonggi-Do, South Korea

    Yeong Shik Kim

Authors
  1. Thien T. P. Dao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kwangho Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jee Young Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yeong Shik Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yeong Shik Kim.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 45516 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dao, T.T.P., Song, K., Kim, J.Y. et al. Igalan from Inula helenium (L.) suppresses the atopic dermatitis-like response in stimulated HaCaT keratinocytes via JAK/STAT3 signaling. Inflamm. Res. 69, 309–319 (2020). https://doi.org/10.1007/s00011-020-01322-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-020-01322-4

Keywords

Search

Navigation