Advertisement

Inflammation

, Volume 41, Issue 2, pp 606–613 | Cite as

Oxymatrine Sensitizes the HaCaT Cells to the IFN-γ Pathway and Downregulates MDC, ICAM-1, and SOCS1 by Activating p38, JNK, and Akt

  • Chun-Jie Gao
  • Pei-Jun Ding
  • Li-Li Yang
  • Xu-Feng He
  • Meng-Jiao Chen
  • Dong-Ming Wang
  • Yan-Xin Tian
  • Hui-Min ZhangEmail author
ORIGINAL ARTICLE

Abstract

Decreased interferon (IFN)-γ levels and increased levels of macrophage-derived chemokine (MDC) and intercellular adhesion molecule (ICAM)-1 are known to be involved in allergic skin diseases, such as eczema and atopic dermatitis. Activation of the IFN-γ and its downstream interleukin-12 (IL-12) pathway can correct these diseases. Suppressor of cytokine signaling 1 (SOCS1) is a cytokine signaling inhibitor that blocks downstream pathways of IFN-γ by blocking the mitogen-activated protein kinase (MAPK) and protein kinase B (Akt) signaling pathways. Oxymatrine (OMT), a quinolizidine alkaloid extracted from the herbal medicine Radix Sophorae flavescentis, is used to treat allergic skin diseases in China. The non-cytotoxic concentrations of OMT in HaCaT cells were determined through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Tumor necrosis factor (TNF)-α and IFN-γ were used to stimulate HaCaT cells, and OMT was added to this system with tacrolimus (FK506) as a positive control. The mRNAs of cytokines, MDC, ICAM-1, IL-12p35, IL-12p40, and IFN-γ receptor (IFN-γR)α were detected by RT-PCR. Western blot analyses were performed to assess activation of the MAPK (p38, Jun N-terminal kinase, and extracellular signal-regulated kinase) and Akt signaling pathways. OMT increased the mRNA levels of the IL-12 and IFN-γRα, reduced the mRNA levels of ICAM-1, MDC, and SOCS1. But FK506 increased the mRNA levels of IL12 and inhibited the expression of ICAM-1 mRNAs and had no effects on the IFN-γRα, MDC, and SOCS1 mRNA in HaCaT cells stimulated with TNF-α and IFN-γ. Thus, the mechanisms through which OMT and FK506 ameliorate allergic skin diseases differ.

KEY WORDS

oxymatrine IFN-γ MAPKs SOCS1 allergic skin diseases atopic dermatitis 

Notes

Funding Information

This work was supported by the National Natural Science Foundation of China (NSFC; Grant No. 81302970/H2709) and the Shanghai Science and Technology Development Funds (Grant No. 13401902504).

Compliance with Ethical Standards

Competing Interests

The authors declare that they have no competing interests.

References

  1. 1.
    Spergel, J.M., E. Mizoguchi, H. Oettgen, A.K. Bhan, and R.S. Geha. 1999. Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. The Journal of Clinical Investigation 103: 1103–1111.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Kawamoto, N., H. Kaneko, M. Takemura, M. Seishima, S. Sakurai, T. Fukao, et al. 2006. Age-related changes in intracellular cytokine profiles and Th2 dominance in allergic children. Pediatric Allergy and Immunology 17: 125–133.CrossRefPubMedGoogle Scholar
  3. 3.
    Herberth, G., J. Heinrich, S. Röder, A. Figl, M. Weiss, U. Diez, et al. 2010. Reduced IFN-gamma- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life. Pediatric Allergy and Immunology 21: 5–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Grassegger, A., and R. Höpfl. 2004. Significance of the cytokine interferon gamma in clinical dermatology. Clinical and Experimental Dermatology 29: 584–588.CrossRefPubMedGoogle Scholar
  5. 5.
    Takakura, M., F. Takeshita, M. Aihara, K.Q. Xin, M. Ichino, K. Okuda, et al. 2005. Hyperproduction of IFN-gamma by CpG oligodeoxynucleotide-induced exacerbation of atopic dermatitis-like skin lesion in some NC/Nga mice. The Journal of Investigative Dermatology 125: 1156–1162.CrossRefPubMedGoogle Scholar
  6. 6.
    Hattori, K., M. Nishikawa, K. Watcharanurak, A. Ikoma, K. Kabashima, H. Toyota, et al. 2010. Sustained exogenous expression of therapeutic levels of IFN-gamma ameliorates atopic dermatitis in NC/Nga mice via Th1 polarization. Journal of Immunology 184: 2729–2735.CrossRefGoogle Scholar
  7. 7.
    Hunter, C.A. 2005. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nature Reviews. Immunology 5: 521–531.CrossRefPubMedGoogle Scholar
  8. 8.
    Trinchieri, G. 2003. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews. Immunology 3: 675–681.CrossRefGoogle Scholar
  9. 9.
    Machura, E., B. Mazur, E. Golemiec, M. Pindel, and F. Halkiewicz. 2008. Staphylococcus aureus skin colonization in atopic dermatitis children is associated with decreased IFN- γ production by peripheral blood CD4 + and CD8 + T cells. Pediatric Allergy & Immunology 19: 37–45.Google Scholar
  10. 10.
    Kakinuma, T., K. Nakamura, M. Wakugawa, H. Mitsui, Y. Tada, H. Saeki, et al. 2001. Thymus and activation-regulated chemokine in atopic dermatitis: serum thymus and activation-regulated chemokine level is closely related with disease activity. The Journal of Allergy and Clinical Immunology 107: 535–541.CrossRefPubMedGoogle Scholar
  11. 11.
    Kakinuma, T., K. Nakamura, M. Wakugawa, H. Mitsui, Y. Tada, H. Saeki, et al. 2002. Serum macrophage-derived chemokine (MDC) levels are closely related with the disease activity of atopic dermatitis. Clinical and Experimental Immunology 127: 270–273.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Lugovic, L., H. Cupic, J. Lipozencic, and J. Jakic-Razumovic. 2006. The role of adhesion molecules in atopic dermatitis. Acta dermatovenerologica Croatica : ADC 14: 2–7.PubMedGoogle Scholar
  13. 13.
    Fenner, J.E., R. Starr, A.L. Cornish, J.G. Zhang, D. Metcalf, R.D. Schreiber, et al. 2005. Suppressor of cytokine signaling 1 regulates the immune response to infection by a unique inhibition of type I interferon activity. Nature Immunology 7: 33–39.CrossRefPubMedGoogle Scholar
  14. 14.
    Qing, Y., A.P. Costa-Pereira, D. Watling, and G.R. Stark. 2005. Role of tyrosine 441 of interferon-γ receptor subunit 1 in SOCS-1-mediated attenuation of STAT1 activation. The Journal of Biological Chemistry 280: 1849–1853.CrossRefPubMedGoogle Scholar
  15. 15.
    Canesi, L., M. Betti, C. Ciacci, B. Citterio, C. Pruzzo, and G. Gallo. 2003. Tyrosine kinase-mediated cell signalling in the activation of Mytilus hemocytes: possible role of STAT-like proteins. Biology of the Cell 95: 603–613.CrossRefPubMedGoogle Scholar
  16. 16.
    Inaba, M., H. Saito, M. Fujimoto, S. Sumitani, T. Ohkawara, T. Tanaka, et al. 2005. Suppressor of cytokine signaling 1 suppresses muscle differentiation through modulation of IGF-I receptor signal transduction. Biochemical and Biophysical Research Communications 328: 953–961.CrossRefPubMedGoogle Scholar
  17. 17.
    Kwon, D.J., Y.S. Bae, S.M. Ju, A.R. Goh, G.S. Youn, S.Y. Choi, et al. 2012. Casuarinin suppresses TARC/CCL17 and MDC/CCL22 production via blockade of NF-κB and STAT1 activation in HaCaT cells. Biochemical & Biophysical Research Communications 417: 1254–1259.CrossRefGoogle Scholar
  18. 18.
    Jeong, S.I., B.M. Choi, and S.I. Jang. 2010. Sulforaphane suppresses TARC/CCL17 and MDC/CCL22 expression through heme oxygenase-1 and NF-κB in human keratinocytes. Archives of Pharmacal Research 33: 1867–1876.CrossRefPubMedGoogle Scholar
  19. 19.
    Tanaka, K., M.H. Roberts, N. Yamamoto, H. Sugiura, M. Uehara, and J.M. Hopkin. 2006. Upregulating promoter polymorphisms of RANTES relate to atopic dermatitis. International Journal of Immunogenetics 33: 423–428.CrossRefPubMedGoogle Scholar
  20. 20.
    Lehmann, B. 1997. HaCaT cell line as a model system for vitamin D3 metabolism in human skin. The Journal of Investigative Dermatology 108: 78–82.CrossRefPubMedGoogle Scholar
  21. 21.
    Brandt, E.B., and U. Sivaprasad. 2011. Th2 cytokines and atopic dermatitis. Journal of Clinical and Cellular Immunology 2: 110.  https://doi.org/10.4172/2155-9899.1000110.
  22. 22.
    Bahar-Shany, K., A. Ravid, and R. Koren. 2010. Upregulation of MMP-9 production by TNFalpha in keratinocytes and its attenuation by vitamin D. Journal of Cellular Physiology 222: 729–737.PubMedGoogle Scholar
  23. 23.
    Roebuck, K.A., and A. Finnegan. 1999. Regulation of intercellular adhesion molecule-1 (CD54) gene expression. Journal of Leukocyte Biology 66: 876–888.CrossRefPubMedGoogle Scholar
  24. 24.
    Sun, L.M., and J. Liu. 2011. Role of oxymatrine associated with glycyrrhizin on immunologic function of T helper cell in patients with eczema. Chinese Journal of Dermatovenereology of Integrated Traditional and Western Medicine 10: 99–101.Google Scholar
  25. 25.
    Shen, Z.H., W.U. Yi Xuan, and W.H. Mao. 2000. Kurarinone injection in treating different types of eczema. Chinese Journal of New Drugs and Clinical Remedies 19: 473–474.Google Scholar
  26. 26.
    Mandelin, J., A. Remitz, H. Virtanen, and S. Reitamo. 2010. One-year treatment with 0.1% tacrolimus ointment versus a corticosteroid regimen in adults with moderate to severe atopic dermatitis: a randomized, double-blind, comparative trial. Acta Dermato-Venereologica 90: 170–174.CrossRefPubMedGoogle Scholar
  27. 27.
    Tu, H.Q., X.Y. Li, M.Y. Tang, J.W. Gao, L.F. Xu, Z.Q. Chen, et al. 2011. Effects of tacrolimus on IFN-γ signaling in keratinocytes: possible mechanisms by which tacrolimus affects IFN-γ-dependent skin inflammation. European Journal of Dermatology Ejd 21: 22–31.PubMedGoogle Scholar
  28. 28.
    Fan, H., Y. Liao, Q. Tang, X.Y. Chen, L.J. Zhang, X.X. Liu, et al. 2012. Role of β2-adrenoceptor-β-arrestin2-nuclear factor-κB signal transduction pathway and intervention effects of oxymatrine in ulcerative colitis. Chinese Journal of Integrative Medicine 18: 514–521.CrossRefPubMedGoogle Scholar
  29. 29.
    Hou, W., H.Y. Liu, X.D. Yang, J.P. Zhou, D. Li, Z.Y. Yang, et al. 2011. Effect of oxymatrine on the distribution of dendritic cells in lung and spleen tissues of asthmatic mice. Chinese Journal of Contemporary Pediatrics 13: 40–43.PubMedGoogle Scholar
  30. 30.
    Xu, M., W. Wang, X. Pei, S. Sun, M. Xu, and Z. Liu. 2014. Protective effects of the combination of sodium ferulate and oxymatrine on cecal ligation and puncture-induced sepsis in mice. Experimental and Therapeutic Medicine 7: 1297–1304.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chang, A., Z. Cai, Z. Wang, and S. Sun. 2014. Extraction and isolation of alkaloids of Sophora alopecuroides and their anti-tumor effects in H22 tumor-bearing mice. African Journal of Traditional, Complementary, and Alternative Medicines 11: 245–248.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Wu, X.S., T. Yang, J. Gu, M.L. Li, W.G. Wu, H. Weng, et al. 2014. Effects of oxymatrine on the apoptosis and proliferation of gallbladder cancer cells. Anti-Cancer Drugs 25: 1007–1015.CrossRefPubMedGoogle Scholar
  33. 33.
    Liao, S., X. Jin, J. Li, T. Zhang, W. Zhang, W. Shi, et al. 2016. Effects of silymarin, glycyrrhizin, and oxymatrine on the pharmacokinetics of ribavirin and its major metabolite in rats. Phytotherapy Research 30: 618–626.CrossRefPubMedGoogle Scholar
  34. 34.
    Shi, L., L. Shi, H. Zhang, Z. Hu, C. Wang, D. Zhang, et al. 2013. Oxymatrine ameliorates non-alcoholic fatty liver disease in rats through peroxisome proliferator-activated receptor-α activation. Molecular Medicine Reports 8: 439–445.CrossRefPubMedGoogle Scholar
  35. 35.
    Wang, Y.P., W. Zhao, R. Xue, Z.X. Zhou, F. Liu, Y.X. Han, et al. 2011. Oxymatrine inhibits hepatitis B infection with an advantage of overcoming drug-resistance. Antiviral Research 89: 227–231.CrossRefPubMedGoogle Scholar
  36. 36.
    Guo, Z.B., Fu JG, and Y. Zhao. 2006. Therapeutic efficacy of oxymatrine on arrhythmia and heart rate variability in patients with coronary heart disease. Chinese Journal of Integrative Medicine 26: 311–315.Google Scholar
  37. 37.
    Lin, M., and L.W. Yang. 2009. Inhibition of the replication of hepatitis B virus in vitro by oxymatrine. The Journal of International Medical Research 37: 1411–1419.CrossRefPubMedGoogle Scholar
  38. 38.
    Durali, D., M.G. de Goer de Herve, J. Giron-Michel, B. Azzarone, J.F. Delfraissy, and Y. Taoufik. 2003. In human B cells, IL-12 triggers a cascade of molecular events similar to Th1 commitment. Blood 102: 4084–4089.CrossRefPubMedGoogle Scholar
  39. 39.
    Simon, M.R., K.D. Cooper, R.B. Norris, B. Blok, and C.L. King. 1995. Antigen presenting cell-independent cytokine and spontaneous in vitro IgE production in patients with atopic dermatitis: increased interferon-γ production and lack of effects of in vivo low-dose interferon-gamma treatment. The Journal of Allergy and Clinical Immunology 96: 84–91.CrossRefPubMedGoogle Scholar
  40. 40.
    Kinjyo, I., T. Hanada, K. Inagaki-Ohara, H. Mori, D. Aki, M. Ohishi, et al. 2002. SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17: 583–591.CrossRefPubMedGoogle Scholar
  41. 41.
    Nold-Petry, C.A., M.F. Nold, J.W. Nielsen, A. Bustamante, J.A. Zepp, K.A. Storm, et al. 2009. Increased cytokine production in interleukin-18 receptor alpha-deficient cells is associated with dysregulation of suppressors of cytokine signaling. The Journal of Biological Chemistry 284: 25900–25911.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yang, J.-H., Y.-H. Hwang, M.-J. Gu, W.-K. Cho, and J.Y. Ma. 2015. Ethanol extracts of Sanguisorba officinalis L. suppress TNF-α/IFN-γ-induced pro-inflammatory chemokine production in HaCaT cells. Phytomedicine 22: 1262–1268.CrossRefPubMedGoogle Scholar
  43. 43.
    Park, J.H., M.S. Kim, G.S. Jeong, and J. Yoon. 2015. Xanthii fructus extract inhibits TNF-α/IFN-γ-induced Th2-chemokines production via blockade of NF-κB, STAT1 and p38-MAPK activation in human epidermal keratinocytes. Journal of Ethnopharmacology 171: 85–93.CrossRefPubMedGoogle Scholar
  44. 44.
    Jang, I.G., J.K. Yang, H.J. Lee, J.Y. Yi, H.O. Kim, C.W. Kim, et al. 2000. Clinical improvement and immunohistochemical findings in severe atopic dermatitis treated with interferon gamma. Journal of the American Academy of Dermatology 42: 1033–1040.CrossRefPubMedGoogle Scholar
  45. 45.
    Noh, G.W., and K.Y. Lee. 1998. Blood eosinophils and serum IgE as predictors for prognosis of interferongamma therapy in atopic dermatitis. Allergy 53: 1202–1207.CrossRefPubMedGoogle Scholar
  46. 46.
    Ellis, C.N., S.R. Stevens, B.K. Blok, R.S. Taylor, and K.D. Cooper. 1999. Interferon-gamma therapy reduces blood leukocyte levels in patients with atopic dermatitis: correlation with clinical improvement. Clinical Immunology 92: 49–55.CrossRefPubMedGoogle Scholar
  47. 47.
    Younes, H.M., and B.G. Amsden. 2002. Interferon-gamma therapy: evaluation of routes of administration and delivery systems. Journal of Pharmaceutical Sciences 91: 2–17.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  • Chun-Jie Gao
    • 1
  • Pei-Jun Ding
    • 1
  • Li-Li Yang
    • 1
  • Xu-Feng He
    • 1
  • Meng-Jiao Chen
    • 1
  • Dong-Ming Wang
    • 1
  • Yan-Xin Tian
    • 1
  • Hui-Min Zhang
    • 1
    Email author
  1. 1.Department of DermatologyShuguang Hospital Affiliated to Shanghai University of Traditional Chinese MedicineShanghaiChina

Personalised recommendations