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Dual role of shikonin in early and late stages of collagen type II arthritis

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Abstract

Objective To investigate the anti-inflammatory or immunomodulatory effect of shikonin on early stage and established murine collagen-induced arthritis (CIA). Methods Mouse were injected intraperitoneally with shikonin (5 mg/kg) for 10 days along before or after the onset of CIA. The arthritis response was monitored visually by macroscopic scoring. Reverse transcription-polymerase chain reaction and western blotting were employed to determine the mRNA and protein expression of cytokine in patella with adjacent synovium in CIA mouse. Histology of knee was used to assess the occurrence of cartilage destruction and bone erosion. Results Shikonin (5 mg/kg) treatment along had no effect on macroscopic score and incidence of arthritis on early stage of CIA. However, a pronounced amelioration of macroscopic score and cartilage destruction was found in mouse treated with shikonin on established CIA for 10 days. Moreover, The mRNA levels of Th1 cytokines [tumor necrosis factor-α and interleukin (IL)-12] was significantly inhibited both in the synovial tissue and in the articular cartilage in treated groups compared with those in control groups, whereas the mRNA and protein levels of Th2 cytokines (IL-10 and IL-4) remained elevated throughout the treatment period. Moreover, the inflammatory cytokine, the mRNA and protein levels of IL-6 was down-regulated in mice with established CIA after treatment with shikonin. T-box expressed in T cells (T-bet) mRNA levels were decreased in shikonin compared with control group, and GATA-3 mRNA levels were higher than that in control group. Conclusion Shikonin treatment on established CIA can inhibit Th1 cytokines expression and induce Th2 cytokines expression in mice with established CIA. The inhibited effect of shikonin on Th1 cytokines expression may be mediated not only by inhibiting Th1 responses through T-bet mechanism, but also by inducing anti-inflammatory mediators such as IL-10 and IL-4 through a GATA-3 dependent mechanism.

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References

  1. Vervoordeldonk MJ, Tak PP (2002) Cytokines in rheumatoid arthritis. Curr Rheumatol Rep 4(3):208–217. doi:10.1007/s11926-002-0067-0

    Article  PubMed  Google Scholar 

  2. Mendoza L (2006) A network model for the control of the differentiation process in Th cells. Biosystems 84(2):101–114. doi:10.1016/j.biosystems.2005.10.004

    Article  PubMed  CAS  Google Scholar 

  3. Okamoto Y, Nishida M (2001) Cytokine balance in the pathogenesis of rheumatoid arthritis. Yakugaku Zasshi 121(2):131–138. doi:10.1248/yakushi.121.131

    Article  PubMed  CAS  Google Scholar 

  4. Moore KW, O’Garra A et al (1993) Interleukin-10. Annu Rev Immunol 11:165–190

    Article  PubMed  CAS  Google Scholar 

  5. Rengarajan J, Szabo SJ et al (2000) Transcriptional regulation of Th1/Th2 polarization. Immunol Today 21:479–483. doi:10.1016/S0167-5699(00)01712-6

    Article  PubMed  CAS  Google Scholar 

  6. Chang HD, Helbig C et al (2007) Expression of IL-10 in Th memory lymphocytes is conditional on IL-12 or IL-4, unless the IL-10 gene is imprinted by GATA-3. Eur J Immunol 37(3):807–817. doi:10.1002/eji.200636385

    Article  PubMed  CAS  Google Scholar 

  7. Szabo SJ, Kim ST et al (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669. doi:10.1016/S0092-8674(00)80702-3

    Article  PubMed  CAS  Google Scholar 

  8. Sun J, Pearce EJ (2007) Suppression of early IL-4 production underlies the failure of CD4 + T cells activated by TLR-stimulated dendritic cells to differentiate into Th2 cells. J Immunol 178(3):1635–1644

    PubMed  CAS  Google Scholar 

  9. Agnello D, Lankford CS et al (2003) Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol 23(3):147–161. doi:10.1023/A:1023381027062

    Article  PubMed  CAS  Google Scholar 

  10. Brand DD, Latham KA et al (2007) Collagen-induced arthritis. Nat Protoc 2(5):1269–1275. doi:10.1038/nprot.2007.173

    Article  PubMed  CAS  Google Scholar 

  11. Pietrosiuk A, Skopińska-Rózewska E et al (2004) Immunomodulatory effect of shikonin derivatives isolated from Lithospermum canescens on cellular and humoral immunity in Balb/c mice. Pharmazie 59(8):640–642

    PubMed  CAS  Google Scholar 

  12. Chen X, Yang L et al (2003) Shikonin, a component of Chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1. Antimicrob Agents Chemother 9(47):2810–2816

    Article  Google Scholar 

  13. Singh B, Sharma MK et al (2003) Anti-inflammatory activity of shikonin derivatives from Arnebia hispidissima. Phytomedicine 10(5):375–380. doi:10.1078/0944-7113-00262

    Article  PubMed  CAS  Google Scholar 

  14. Bernard P, Leung B et al (2004) Combined effects of IL-12 and IL-18 on the induction of collagen-induced arthritis. Clin Exp Immunol 136:440–447. doi:10.1111/j.1365-2249.2004.02430.x

    Article  Google Scholar 

  15. Yamaguchi Y, Fujio K et al (2007) IL–17B and IL–17C are associated with TNF-alpha production and contribute to the exacerbation of inflammatory arthritis. J Immunol 179(10):7128–7136

    PubMed  CAS  Google Scholar 

  16. Nirmal K, Damian M et al (2003) Prevention of collagen-induced arthritis in mice transgenic for the complement inhibitor complement receptor 1-related gene/protein. J Immunol 171:2109–2115

    Google Scholar 

  17. Smeets RL, van de Loo FAJ et al (2003) Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice. Gene Ther 10:1004–1011. doi:10.1038/sj.gt.3301986

    Article  PubMed  CAS  Google Scholar 

  18. Gao B, Fang D et al (2006) The pro-inflammatory cytokines IL–1β and TNF-α induce the expression of Synoviolin, an E3 ubiquitin ligase, in mouse synovial fibroblasts via the Erk1/2-ETS1 pathway. Arthritis Res Ther 172:1186–2011

    Google Scholar 

  19. Dulos J, Verbraak E (2004) Severity of murine collagen-induced arthritis correlates with increased CYP7B activity. Arthritis Rheum 50(10):3346–3353. doi:10.1002/art.20509

    Article  PubMed  CAS  Google Scholar 

  20. Kristine A, Kuhn L et al (2006) Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J Clin Invest 116:961–973. doi:10.1172/JCI25422

    Article  Google Scholar 

  21. Staniforth V, Wang S-Y et al (2004) Shikonins, phytocompounds from Lithospermum erythrorhizon, inhibit the transcriptional activation of human tumor necrosis factor α promoter in vivo. J Biol Chem 7(279):5877–5885

    Google Scholar 

  22. Chen X, Oppenheim J et al (2001) Shikonin, a component of anti-inflammatory Chinese herbal medicine, selectively blocks chemokine binding to CC chemokine receptor-1. Int Immunopharmacol 1(2):229–236. doi:10.1016/S1567-5769(00)00033-3

    Article  PubMed  CAS  Google Scholar 

  23. Ishida T, Sakaguchi I (2007) Protection of human keratinocytes from UVB-induced inflammation using root extract of Lithospermum erythrorhizon. Biol Pharm Bull 30(5):928–934. doi:10.1248/bpb.30.928

    Article  PubMed  CAS  Google Scholar 

  24. Yu-Hsiang HSU, Hsing-Hui LI et al (2006) Function of interleukin-20 as a proinflammatory molecule in rheumatoid and experimental arthritis. Arthritis Rheum 54(9):2722–2733. doi:10.1002/art.22039

    Article  Google Scholar 

  25. Kageyama Y, Koide Y et al (2004) Plasmid encoding interleukin-4 in the amelioration of murine collagen-induced arthritis. Arthritis Rheum 50(3):968–975. doi:10.1002/art.20107

    Article  PubMed  CAS  Google Scholar 

  26. Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2:933–944. doi:10.1038/nri954

    Article  PubMed  CAS  Google Scholar 

  27. Szabo SJ, Sullivan BM et al (2003) Molecular mechanisms regulating Th1 immune responses. Annu Rev Immunol 21:713–758. doi:10.1146/annurev.immunol.21.120601.140942

    Article  PubMed  CAS  Google Scholar 

  28. Chakir H, Wang H et al (2003) T-bet/GATA-3 ratio as a measure of the Th1/Th2 cytokine profile in mixed cell populations. predominant role of GATA-3. J Immunol Methods 278:157–169. doi:10.1016/S0022-1759(03)00200-X

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Acknowledgments

The authors thank Y. Li, Ph.D. (Department of rheumatology, The Second Affiliated Hospital, Harbin Medical University, Harbin, China) for her help in conducting the study and for reviewing the manuscript. This work were supported by the Science Foundation of Heilongjiang traditional Chinese medicine university and Dr Science Foundation of Harbin Medical University.

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Authors and Affiliations

  1. Department of Rheumatology, The Second Affiliated Hospital, Harbin Medical University, Bao Jian Road, Harbin, 150086, People’s Republic of China

    Qiaomei Dai & Feng-shan Zhang

  2. Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada

    Jianghong Fang

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  1. Qiaomei Dai
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  2. Jianghong Fang
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Correspondence to Feng-shan Zhang.

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Dai, Q., Fang, J. & Zhang, Fs. Dual role of shikonin in early and late stages of collagen type II arthritis. Mol Biol Rep 36, 1597–1604 (2009). https://doi.org/10.1007/s11033-008-9356-7

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  • DOI: https://doi.org/10.1007/s11033-008-9356-7

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