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Embelin Suppresses Dendritic Cell Functions and Limits Autoimmune Encephalomyelitis Through the TGF-β/β-catenin and STAT3 Signaling Pathways

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Abstract

Embelin (2,5-dihydroxy-3-undecyl-1,4-benzoquinone, EB) has been shown to inhibit the X-linked inhibitor of apoptosis protein and various inflammatory pathways. Although different molecular mechanisms have been described for the potent antitumor activities of EB, its potential effect on inflammatory and immune-mediated diseases such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) remains unclear. In this study, we demonstrated that EB suppressed human CD14+ monocyte-derived dendritic cell (DC) differentiation, maturation, and endocytosis and further inhibited the stimulatory function of mature DCs on allogeneic T cell proliferation in vitro. In addition, EB blocked the DC-derived expression of the Th1 cell-polarizing cytokines interferon-γ and interleukin (IL)-12 and the Th17 cell-polarizing cytokines IL-6 and IL-23. In vivo administration of EB led to a reduction in the EAE clinical score, in central nervous system inflammation, and in demyelination. Furthermore, EB also suppressed inflammatory Th1 and Th17 cells in EAE, at least partially, through the promotion of transforming growth factor-beta and β-catenin expression and inhibition of signal transducer and activator of transcription 3 signaling pathways in DCs. These data suggest that EB has potent anti-inflammatory and immunosuppressive properties and is a potential therapeutic drug for MS and other autoimmune inflammatory diseases.

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Abbreviations

EB:

Embelin

MS:

Multiple sclerosis

EAE:

Experimental autoimmune encephalomyelitis

iDC:

Immature dendritic cell

mDC:

Mature dendritic cell

References

  1. Gupta OP, Ali MM, Ray Ghatak BJ, Atal CK (1977) Some pharmacological investigations of embelin and its semisynthetic derivatives. Indian J Physiol Pharmacol 21:31–39

    CAS  PubMed  Google Scholar 

  2. Chitra M, Sukumar E, Devi CS (1995) [3H]-thymidine uptake and lipid peroxidation by tumor cells on embelin treatment: an in vitro study. Oncology 52:66–68

    Article  CAS  PubMed  Google Scholar 

  3. Nikolovska-Coleska Z, Xu L, Hu Z, Tomita Y, Li P, Roller PP, Wang R, Fang X, Guo R, Zhang M, Lippman ME, Yang D, Wang S (2004) Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database. J Med Chem 47:2430–2440

    Article  CAS  PubMed  Google Scholar 

  4. Ahn KS, Sethi G, Aggarwal BB (2007) Embelin, an inhibitor of X chromosome-linked inhibitor-of-apoptosis protein, blocks nuclear factor-kappaB (NF-kappaB) signaling pathway leading to suppression of NF-kappaB-regulated antiapoptotic and metastatic gene products. Mol Pharmacol 71:209–219

    Article  CAS  PubMed  Google Scholar 

  5. Sasaki Y, Minamizawa M, Ambo A, Sugawara S, Ogawa Y, Nitta K (2008) Cell-penetrating peptide-conjugated XIAP-inhibitory cyclic hexapeptides enter into Jurkat cells and inhibit cell proliferation. Febs J 275:6011–6021

    Article  CAS  PubMed  Google Scholar 

  6. Mori T, Doi R, Kida A, Nagai K, Kami K, Ito D, Toyoda E, Kawaguchi Y, Uemoto S (2007) Effect of the XIAP inhibitor embelin on TRAIL-induced apoptosis of pancreatic cancer cells. J Surg Res 142:281–286

    Article  CAS  PubMed  Google Scholar 

  7. Mareninova OA, Sung KF, Hong P, Lugea A, Pandol SJ, Gukovsky I, Gukovskaya AS (2006) Cell death in pancreatitis: caspases protect from necrotizing pancreatitis. J Biol Chem 281:3370–3381

    Article  CAS  PubMed  Google Scholar 

  8. Aird KM, Ding X, Baras A, Wei J, Morse MA, Clay T, Lyerly HK, Devi GR (2008) Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression. Mol Cancer Ther 7:38–47

    Article  CAS  PubMed  Google Scholar 

  9. Dai Y, Qiao L, Chan KW, Yang M, Ye J, Ma J, Zou B, Gu Q, Wang J, Pang R, Lan HY, Wong BC (2009) Peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of embelin on colon carcinogenesis. Cancer Res 69:4776–4783

    Article  CAS  PubMed  Google Scholar 

  10. Heo JY, Kim HJ, Kim SM, Park KR, Park SY, Kim SW, Nam D, Jang HJ, Lee SG, Ahn KS, Kim SH, Shim BS, Choi SH (2011) Embelin suppresses STAT3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase PTEN. Cancer Lett 308:71–80

    Article  CAS  PubMed  Google Scholar 

  11. Dai Y, Desano J, Qu Y, Tang W, Meng Y, Lawrence TS, Xu L (2011) Natural IAP inhibitor embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer. Am J Cancer Res 1:128–143

    CAS  PubMed Central  PubMed  Google Scholar 

  12. Xu M, Cui J, Fu H, Proksch P, Lin W, Li M (2005) Embelin derivatives and their anticancer activity through microtubule disassembly. Planta Med 71:944–948

    Article  CAS  PubMed  Google Scholar 

  13. Kim SW, Kim SM, Bae H, Nam D, Lee JH, Lee SG, Shim BS, Kim SH, Ahn KS, Choi SH, Sethi G, Ahn KS (2013) Embelin inhibits growth and induces apoptosis through the suppression of Akt/mTOR/S6K1 signaling cascades. Prostate 73(3):296–305

    Article  CAS  PubMed  Google Scholar 

  14. Gandhi GR, Stalin A, Balakrishna K, Ignacimuthu S, Paulraj MG, Vishal R (2013) Insulin sensitization via partial agonism of PPARγ and glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway by embelin in type 2 diabetic rats. Biochim Biophys Acta 1830(1):2243–2255

    Article  CAS  PubMed  Google Scholar 

  15. Banchereau J, Steinman RM (1998) Dendritic cells and the control of immunity. Nature 392:245–252

    Article  CAS  PubMed  Google Scholar 

  16. Pulendran B (2004) Modulating vaccine responses with dendritic cells and Toll-like receptors. Immunol Rev 199:227–250

    Article  CAS  PubMed  Google Scholar 

  17. Steinman RM, Hawiger D, Nussenzweig MC (2003) Tolerogenic dendritic cells. Annu Rev Immunol 21:685–711

    Article  CAS  PubMed  Google Scholar 

  18. Mellman I, Steinman RM (2001) Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255–258

    Article  CAS  PubMed  Google Scholar 

  19. Trombetta ES, Mellman I (2005) Cell biology of antigen processing in vitro and in vivo. Annu Rev Immunol 23:975–1028

    Article  CAS  PubMed  Google Scholar 

  20. Engelhardt B (2008) Immune cell entry into the central nervous system: involvement of adhesion molecules and chemokines. J Neurol Sci 274:23–26

    Article  CAS  PubMed  Google Scholar 

  21. Goverman J (2009) Autoimmune T cell responses in the central nervous system. Nat Rev Immunol 9:393–407

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Hamann I, Zipp F, Infante-Duarte C (2008) Therapeutic targeting of chemokine signaling in multiple sclerosis. J Neurol Sci 274:31–38

    Article  CAS  PubMed  Google Scholar 

  23. Cua DJ, Hinton DR, Stohlman SA (1995) Self-antigen-induced Th2 responses in experimental allergic encephalomyelitis (EAE)-resistant mice. Th2-mediated suppression of autoimmune disease. J Immunol 155(8):4052–4059

    CAS  PubMed  Google Scholar 

  24. Krishnamoorthy G, Wekerle H (2009) EAE: an immunologist’s magic eye. Eur J Immunol 39:2031–2035

    Article  CAS  PubMed  Google Scholar 

  25. Bai XF, Shi FD, Xiao BG, Li HL, van der Meide PH, Link H (1997) Nasal administration of myelin basic protein prevents relapsing experimental autoimmune encephalomyelitis in DA rats by activating regulatory cells expressing IL-4 and TGF-beta mRNA. J Neuroimmunol 80(1–2):65–75

    Article  CAS  PubMed  Google Scholar 

  26. Johns LD, Flanders KC, Ranges GE, Sriram S (1991) Successful treatment of experimental allergic encephalomyelitis with transforming growth factor-β1. J Immunol 147:1792–1796

    CAS  PubMed  Google Scholar 

  27. Racke MK, Dhib-Jalbut S, Cannella B, Albert PS, Raine CS, McFarlin DE (1991) Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol 146(9):3012–3017

    CAS  PubMed  Google Scholar 

  28. Racke MK, Cannella B, Albert P, Sporn M, Raine CS, McFarlin DE (1992) Evidence of endogenous regulatory function of transforming growth factor-beta 1 in experimental allergic encephalomyelitis. Int Immunol 4(5):615–620

    Article  CAS  PubMed  Google Scholar 

  29. Kuruvilla AP, Shah R, Hochwald GM, Liggitt HD, Palladino MA, Thorbecke GJ (1991) Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci U S A 88(7):2918–2921

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Johns LD, Sriram S (1993) Experimental allergic encephalomyelitis: neutralizing antibody to TGF beta 1 enhances the clinical severity of the disease. J Neuroimmunol 47(1):1–7

    Article  CAS  PubMed  Google Scholar 

  31. Issazadeh S, Mustafa M, Ljungdahl A, Höjeberg B, Dagerlind A, Elde R, Olsson T (1995) Interferon gamma, interleukin 4 and transforming growth factor beta in experimental autoimmune encephalomyelitis in Lewis rats: dynamics of cellular mRNA expression in the central nervous system and lymphoid cells. J Neurosci Res 40(5):579–590

    Article  CAS  PubMed  Google Scholar 

  32. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170

    Article  CAS  PubMed  Google Scholar 

  33. Laouar Y, Town T, Jeng D, Tran E, Wan Y, Kuchroo VK, Flavell RA (2008) TGF-beta signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 105(31):10865–10870

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Fu C, Jiang A (2010) Generation of tolerogenic dendritic cells via the E-cadherin/beta-catenin-signaling pathway. Immunol Res 46:72–78

    Article  CAS  PubMed  Google Scholar 

  35. Ding Y, Shen S, Lino AC, Curotto de Lafaille MA, Lafaille JJ (2008) Beta-catenin stabilization extends regulatory T cell survival and induces anergy in nonregulatory T cells. Nat Med 14(2):162–169

    Article  CAS  PubMed  Google Scholar 

  36. Valenta T, Hausmann G, Basler K (2012) The many faces and functions of β-catenin. EMBO J 31(12):2714–2736

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781–810

    Article  CAS  PubMed  Google Scholar 

  38. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A (2009) Adipogenesis and WNT signalling. Trends Endocrinol Metab 20:16–24

    Article  CAS  PubMed  Google Scholar 

  39. Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X, He X (2002) Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108:837–847

    Article  CAS  PubMed  Google Scholar 

  40. Vander Lugt B, Beck ZT, Fuhlbrigge RC, Hacohen N, Campbell JJ, Boes M (2011) TGF-β suppresses β-catenin-dependent tolerogenic activation program in dendritic cells. PLoS One 6(5):e20099

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Loma I, Heyman R (2011) Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol 9(3):409–416

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Stromnes IM, Goverman JM (2006) Active induction of experimental allergic encephalomyelitis. Nat Protoc 1(4):1810–1819

    Article  CAS  PubMed  Google Scholar 

  43. Manicassamy S, Reizis B, Ravindran R, Nakaya H, Salazar-Gonzalez RM, Wang YC, Pulendran B (2010) Activation of beta-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329(5993):849–853

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S (1998) Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10(12):1969–1980

    Article  CAS  PubMed  Google Scholar 

  45. Shevach EM (2000) Regulatory T cells in autoimmmunity. Annu Rev Immunol 18:423–449

    Article  CAS  PubMed  Google Scholar 

  46. Curotto de Lafaille MA, Lafaille JJ (2009) Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30(5):626–635

    Article  CAS  PubMed  Google Scholar 

  47. Stambolic V, Ruel L, Woodgett JR (1996) Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr Biol 6:1664–1668

    Article  CAS  PubMed  Google Scholar 

  48. Levine S, Saltzman A (1991) Inhibition of experimental allergic encephalomyelitis by lithium chloride: specific effect or nonspecific stress? Immunopharmacology 22(3):207–213

    Article  CAS  PubMed  Google Scholar 

  49. Zhu Z, Kremer P, Tadmori I, Ren Y, Sun D, He X, Young W (2011) Lithium suppresses astrogliogenesis by neural stem and progenitor cells by inhibiting STAT3 pathway independently of glycogen synthase kinase 3 beta. PLoS One 6(9):e23341

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Wang XH, Meng XW, Xing H, Qu B, Han MZ, Chen J, Fan YJ, Lu CQ, Lu ZW (2011) STAT3 and beta-catenin signaling pathway may affect GSK-3beta expression in hepatocellular carcinoma. Hepato gastroenterology 58(106):487–491

    CAS  PubMed  Google Scholar 

  51. Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29(2):95–102

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the Tianjin Blood Center for providing us with the buffy coat. We also thank the Experimental Animal Center of Tianjin Medical University (Tianjin, China) for their work in animal husbandry. This work is supported by the Ministry of Science and Technology of China through grant nos. 2012CB932503 and 2012CBA01305, the National Natural Science Foundation of China through grant nos. 91029705, 81272317, and 81172864, and the Natural Science Foundation of Tianjin through grant no. 12JCZDJC23500.

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Authors and Affiliations

  1. Laboratory of Immunology and Inflammation, Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China

    Zhenyi Xue, Zhenzhen Ge, Kai Zhang, Rui Sun, Rong Han, Meiyu Peng, Yan Li, Wen Li, Yurong Da & Rongxin Zhang

  2. Department of Immunology, Basic Medical College, Tianjin Medical University, Tianjin, 300070, China

    Zhenyi Xue, Zhenzhen Ge, Kai Zhang, Meiyu Peng, Yan Li, Wen Li, Yurong Da, Zhi Yao & Rongxin Zhang

  3. Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, 300070, China

    Zhenyi Xue, Zhenzhen Ge, Kai Zhang, Meiyu Peng, Yan Li, Wen Li, Yurong Da, Zhi Yao & Rongxin Zhang

  4. Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Medical University, Tianjin, 300070, China

    Zhenyi Xue, Zhenzhen Ge, Kai Zhang, Meiyu Peng, Yan Li, Wen Li, Yurong Da, Zhi Yao & Rongxin Zhang

  5. Tianjin Metabolic Diseases Hospital, Tianjin Medical University, Tianjin, 300070, China

    Juhong Yang

  6. School of Medical Imaging, Tianjin Medical University, Tianjin, 300070, China

    Da Zhang

  7. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China

    Junwei Hao

  8. Center for Basic Medical Science Research, Tianjin Medical University, Tianjin, 300070, China

    Rongxin Zhang

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  1. Zhenyi Xue
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  2. Zhenzhen Ge
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  3. Kai Zhang
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  4. Rui Sun
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  8. Yan Li
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  10. Da Zhang
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Correspondence to Zhi Yao or Rongxin Zhang.

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Zhenyi Xue, Zhenzhen Ge, and Kai Zhang contributed equally to this work.

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Xue, Z., Ge, Z., Zhang, K. et al. Embelin Suppresses Dendritic Cell Functions and Limits Autoimmune Encephalomyelitis Through the TGF-β/β-catenin and STAT3 Signaling Pathways. Mol Neurobiol 49, 1087–1101 (2014). https://doi.org/10.1007/s12035-013-8583-7

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