, Volume 41, Issue 1, pp 154–163 | Cite as

Anti-IL-33 Antibody Has a Therapeutic Effect in an Atopic Dermatitis Murine Model Induced by 2, 4-Dinitrochlorobenzene

  • Ge Peng
  • Zhenzhen Mu
  • Lixia Cui
  • Pengyue Liu
  • Ying Wang
  • Wenqing Wu
  • Xiuping Han


IL-33 is a new member of the IL-1 family that plays a role in allergic disease. In this study, we evaluated the potential on the inhibition of atopic dermatitis (AD) of anti-mouse IL-33 antibody (αIL-33Ab) using 2, 4-dinitrochlorobenzene (DNCB)-induced AD mice model. We treated mice with αIL-33Ab via subcutaneous injection of each DNCB treatment 1 h later from day 1 to day 33 for 14 times. A control group received tacrolimus. Skin lesion and scratching behavior were compared. Ear thickness, dermatitis score, eosinophils and mast cells infiltration, and serum IgE levels were also analyzed. Correlations between serum IL-33 as well as soluble(s) ST2 and AD disease activity index in human AD were also investigated. DNCB-induced AD-like mice treated with αIL-33Ab showed improved AD-like symptoms. Eosinophils and mast cells infiltration and serum IgE levels were also significantly reduced by αIL-33Ab. Our study suggests that blockade of IL-33 has a curative effect on AD.


IL-33 αIL-33Ab atopic dermatitis DNCB inhibition 


Funding Information

This work was supported by Scientific Research General Project of Educational Department in Liaoning Province of China in 2014 (Grant No. L2014295) and Science and Technology Project of Shenyang (Grant No. 17-230-9-25). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with Ethical Standards

The study adhered to the tenets of the Declaration of Helsinki. The study was approved by the local ethical committee (2016PS001K) and oral consent was obtained from all individuals.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

10753_2017_673_MOESM1_ESM.docx (706 kb)
Suppl. 1 (DOCX 705 kb)


  1. 1.
    Weidinger, S., and N. Novak. 2016. Atopic dermatitis. Lancet 387 (10023): 1109–1122. Scholar
  2. 2.
    Karuppagounder, V., S. Arumugam, R.A. Thandavarayan, V. Pitchaimani, R. Sreedhar, R. Afrin, M. Harima, H. Suzuki, M. Nomoto, S. Miyashita, K. Suzuki, M. Nakamura, K. Ueno, and K. Watanabe. 2015. Tannic acid modulates NF휅B signaling pathway and skin inflammation in NC/Nga mice through PPAR훾 expression. Cytokine 76 (2): 206–213. Scholar
  3. 3.
    Liu, F.T., H. Goodarzi, and H.Y. Chen. 2011. IgE, mast cells, and eosinophils in atopic dermatitis. Clinical Reviews in Allergy & Immunology 41 (3): 298–310. Scholar
  4. 4.
    Numerof, R.P., and K. Asadullah. 2006. Cytokine and anti-cytokine therapies for psoriasis and atopic dermatitis. BioDrugs 20 (2): 93–103.CrossRefPubMedGoogle Scholar
  5. 5.
    Molfino, N.A., D. Gossage, R. Kolbeck, J.M. Parker, and G.P. Geba. 2012. Molecular and clinical rationale for therapeutic targeting of interleukin-5 and its receptor. Clinical and Experimental Allergy 42 (5): 712–737. Scholar
  6. 6.
    Di Lernia, V. 2015. Therapeutic strategies in extrinsic atopic dermatitis: focus on inhibition of IL-4 as a new pharmacological approach. Expert Opinion on Therapeutic Targets 19 (1): 87–96. Scholar
  7. 7.
    Chow, J.Y., C.K. Wong, P.F. Cheung, and C.W. Lam. 2010. Intracellular signaling mechanisms regulating the activation of human eosinophils by the novel Th2 cytokine IL-33: implications for allergic inflammation. Cellular & Molecular Immunology 7 (1): 26–34. Scholar
  8. 8.
    Olivry, T., D. Mayhew, J.S. Paps, K.E. Linder, C. Peredo, D. Rajpal, H. Hofland, and J. Cote-Sierra. 2016. Early activation of Th2/Th22 inflammatory and pruritogenic pathways in acute canine atopic dermatitis skin lesions. The Journal of Investigative Dermatology 136 (10): 1961–1969. Scholar
  9. 9.
    Schmitz, J., A. Owyang, E. Oldham, Y. Song, E. Murphy, T.K. McClanahan, G. Zurawski, M. Moshrefi, J. Qin, X. Li, D.M. Gorman, J.F. Bazan, and R.A. Kastelein. 2005. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23 (5): 479–490.CrossRefPubMedGoogle Scholar
  10. 10.
    Liew, F.Y., N.I. Pitman, and I.B. McInnes. 2010. Disease-associated functions of IL-33: the new kid in the IL-1 family. Nature Reviews. Immunology 10 (2): 103–110. Scholar
  11. 11.
    Saluja, R., M.E. Ketelaar, T. Hawro, M.K. Church, M. Maurer, and M.C. Nawijn. 2015. The role of the IL-33/IL-1RL1 axis in mast cell and basophil activation in allergic disorders. Molecular Immunology 63 (1): 80–85. Scholar
  12. 12.
    Iikura, M., H. Suto, N. Kajiwara, K. Oboki, T. Ohno, Y. Okayama, H. Saito, S.J. Galli, and S. Nakae. 2007. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Laboratory Investigation 87 (10): 971–978.CrossRefPubMedGoogle Scholar
  13. 13.
    Pecaric-Petkovic, T., S.A. Didichenko, S. Kaempfer, N. Spiegl, and C.A. Dahinden. 2009. Human basophils and eosinophils are the direct target leukocytes of the novel IL-1 family member IL-33. Blood 113 (7): 1526–1534. Scholar
  14. 14.
    Kroeger, K.M., B.M. Sullivan, and R.M. Locksley. 2009. IL-18 and IL-33 elicit Th2 cytokines from basophils via a MyD88- and p38alpha-dependent pathway. Journal of Leukocyte Biology 86 (4): 769–778. Scholar
  15. 15.
    Saluja, R., A. Zoltowska, M.E. Ketelaar, and G. Nilsson. 2016. IL-33 and thymic stromal lymphopoietin in mast cell functions. European Journal of Pharmacology 778: 68–76. Scholar
  16. 16.
    Li, C., I. Maillet, C. Mackowiak, C. Viala, F. Di Padova, M. Li, D. Togbe, V. Quesniaux, Y. Lai, and B. Ryffel. 2017. Experimental atopic dermatitis depends on IL-33R signaling via MyD88 in dendritic cells. Cell Death & Disease 8 (4): e2735. Scholar
  17. 17.
    Mizutani, N., T. Nabe, and S. Yoshino. 2013. Interleukin-33 and alveolar macrophages contribute to the mechanisms underlying the exacerbation of IgE-mediated airway inflammation and remodelling in mice. Immunology 139 (2): 205–218. Scholar
  18. 18.
    Hanifin, J.M., and G. Rajka. 1980. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 92 (Suppl): 44–47.Google Scholar
  19. 19.
    Severity scoring of atopic dermatitis: the SCORAD index. 1993. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology 186(1):23–31.Google Scholar
  20. 20.
    Kilkenny, C., W. Browne, I.C. Cuthill, M. Emerson, D.G. Altman, and NC3Rs Reporting Guidelines Working Group. 2010. Animal research: reporting in vivo experiments: the ARRIVE guidelines. British Journal of Pharmacology 160 (7): 1577–1579. Scholar
  21. 21.
    McGrath, J., G. Drummond, E. Mclachlan, C. Kilkenny, and C.L. Wainwright. 2010. Guidelines for reporting experiments involving animals: the ARRIVE guidelines. British Journal of Pharmacology 160 (7): 1573–1576. Scholar
  22. 22.
    Kim, H., J.R. Kim, H. Kang, J. Choi, H. Yang, P. Lee, J. Kim, and K.W. Lee. 2014. 7,8,4′-Trihydroxyisoflavone attenuates DNCB-induced atopic dermatitis-like symptoms in NC/Nga mice. PLoS One 9 (8): e104938. Scholar
  23. 23.
    Yamashita, H., T. Makino, H. Mizukami, and M. Nose. 2007. Pharmacological characterization of a chronic pruritus model induced by multiple application of 2, 4, 6-trinitrochlorobenzene in NC mice. European Journal of Pharmacology 563: 233–239.CrossRefPubMedGoogle Scholar
  24. 24.
    Leung, D.Y., R.L. Hirsch, L. Schneider, C. Moody, R. Takaoka, S.H. Li, L.A. Meyerson, S.G. Mariam, G. Goldstein, and J.M. Hanifin. 1990. Thymopentin therapy reduces the clinical severity of atopic dermatitis. The Journal of Allergy and Clinical Immunology 85 (5): 927–933.CrossRefPubMedGoogle Scholar
  25. 25.
    Jo, S., J. Ryu, H. Kim, M. Kim, M.H. Ryu, H. Kim, and S.I. Cho. 2015. Anti-inflammatory effects of Sanguisorbae Radix on contact dermatitis induced by dinitrofluorobenzene in mice. Chinese Journal of Integrative Medicine.
  26. 26.
    Lu, Y., J.H. Yang, X. Li, K. Hwangbo, S.L. Hwang, Y. Taketomi, M. Murakami, Y.C. Chang, C.H. Kim, J.K. Son, and H.W. Chang. 2011. Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochemical Pharmacology 82 (11): 1700–1708. Scholar
  27. 27.
    Brandt EB, Sivaprasad U. 2011. Th2 cytokines and atopic dermatitis. J Clin Cell Immunol. 2(3). doi:
  28. 28.
    Lu, Y., Y. Li, M. Jin, J.H. Yang, X. Li, G.H. Chao, H.H. Park, Y.N. Park, J.K. Son, E. Lee, and H.W. Chang. 2012. Inula japonica extract inhibits mast cell-mediated allergic reaction and mast cell activation. Journal of Ethnopharmacology 143 (1): 151–157. Scholar
  29. 29.
    Kawakami, T., T. Ando, M. Kimura, B.S. Wilson, and Y. Kawakami. 2009. Mast cells in atopic dermatitis. Current Opinion in Immunology 21 (6): 666–678. Scholar
  30. 30.
    Leung, D.Y. 2000. Atopic dermatitis: new insights and opportunities for therapeutic intervention. The Journal of Allergy and Clinical Immunology 105 (5): 860–876. Scholar
  31. 31.
    Beck, L.A., and D.Y. Leung. 2000. Allergen sensitization through the skin induces systemic allergic responses. The Journal of Allergy and Clinical Immunology 106 (5 Suppl): S258–S263.CrossRefPubMedGoogle Scholar
  32. 32.
    Tamagawa-Mineoka, R., Y. Okuzawa, K. Masuda, and N. Katoh. 2014. Increased serum levels of interleukin 33 in patients with atopic dermatitis. Journal of the American Academy of Dermatology 70 (5): 882–888. Scholar
  33. 33.
    Savinko, T., S. Matikainen, U. Saarialho-Kere, M. Lehto, G. Wang, S. Lehtimäki, P. Karisola, T. Reunala, H. Wolff, A. Lauerma, and H. Alenius. 2012. IL-33 and ST2 in atopic dermatitis: expression profiles and modulation by triggering factors. The Journal of Investigative Dermatology 132 (5): 1392–1400. Scholar
  34. 34.
    Vocca, L., C. Di Sano, C.G. Uasuf, A. Sala, L. Riccobono, S. Gangemi, G.D. Albano, A. Bonanno, R. Gagliardo, and M. Profita. 2015. IL-33/ST2 axis controls Th2/IL-31 and Th17 immune response in allergic airway diseases. Immunobiology 220 (8): 954–963. Scholar
  35. 35.
    Hamzaoui, A., A. Berraies, W. Kaabachi, M. Haifa, J. Ammar, and H. Kamel. 2013. Induced sputum levels of IL-33 and soluble ST2 in young asthmatic children. The Journal of Asthma 50 (8): 803–809. Scholar
  36. 36.
    Nygaard, U., M. Hvid, C. Johansen, M. Buchner, R. Fölster-Holst, M. Deleuran, and C. Vestergaard. 2016. TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis. Journal of the European Academy of Dermatology and Venereology 30 (11): 1930–1938. Scholar
  37. 37.
    Hayakawa, H., M. Hayakawa, A. Kume, and S. Tominaga. 2007. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. The Journal of Biological Chemistry 282: 26369–26380.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of DermatologyShengjing Hospital of China Medical UniversityShenyangChina

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