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Article

Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells

  • Authors:
    • Ting‑Wen Chung
    • Yi‑Rong Li
    • Wei Yuan Huang
    • Jui‑Hsin Su
    • Hong‑Lin Chan
    • Sheng‑Hao Lin
    • Chin‑San Liu
    • Shih‑Chao Lin
    • Chi‑Chien Lin
    • Ching‑Hsiung Lin
  • View Affiliations / Copyright

    Affiliations: Institute of Bioinformatics and Structural Biology and Department of Medical Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan, R.O.C., Department of Medical Research, Changhua Christian Hospital, Changhua 50006, Taiwan, R.O.C., Institute of Biomedical Science, National Chung‑Hsing University, Taichung 40227, Taiwan, R.O.C., National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan, R.O.C., Institute of Genomics and Bioinformatics, National Chung‑Hsing University, Taichung 40227, Taiwan, R.O.C.
  • Pages: 6992-7000
    |
    Published online on: September 13, 2017
       https://doi.org/10.3892/mmr.2017.7480
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Abstract

The dendritic cell (DC) maturation process is essential for the development of T cell responses and immune tolerance. Accordingly, DCs are considered a major target in the development of immunomodulating agents. In the present study, the effect of sinulariolide, an active compound isolated from the cultured soft coral Sinularia flexibilis, on lipopolysaccharide (LPS)‑induced murine bone marrow‑derived DCs was evaluated. The different phenotypes, cytokine secretion and the mix‑lymphocyte reaction of DCs were detected using flow cytometry and ELISA. The experimental results revealed that the phenotypic and functional maturation of DCs stimulated by LPS were markedly reduced by sinulariolide in a concentration‑dependent manner, including the expression of co‑stimulatory molecules (CD40, CD80 and CD86). In addition, sinulariolide reduced the release of tumor necrosis factor‑α, interleukin (IL)‑6, IL‑12 and nitric oxide from the LPS‑activated DCs, decreased their abilities to stimulate allogeneic T cell proliferation, and inhibited LPS‑induced nuclear factor‑κB pathways. These findings offer novel insight into the immunopharmacological function of sinulariolide and its effects on DCs.
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1 

Li X, He X, Liu B, Xu L, Lu C, Zhao H, Niu X, Chen S and Lu A: Maturation of murine bone marrow-derived dendritic cells induced by Radix Glycyrrhizae polysaccharide. Molecules. 17:6557–6568. 2012. View Article : Google Scholar : PubMed/NCBI

2 

Kim GY, Lee MY, Lee HJ, Moon DO, Lee CM, Jin CY, Choi YH, Jeong YK, Chung KT, Lee JY, et al: Effect of water-soluble proteoglycan isolated from Agaricus blazei on the maturation of murine bone marrow-derived dendritic cells. Int Immunopharmacol. 5:1523–1532. 2005. View Article : Google Scholar : PubMed/NCBI

3 

English K, Barry FP and Mahon BP: Murine mesenchymal stem cells suppress dendritic cell migration, maturation and antigen presentation. Immunol Lett. 115:50–58. 2008. View Article : Google Scholar : PubMed/NCBI

4 

Hackstein H and Thomson AW: Dendritic cells: Emerging pharmacological targets of immunosuppressive drugs. Nat Rev Immunol. 4:24–34. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Li G, Zhang Y, Deng Z, van Ofwegen L, Proksch P and Lin W: Cytotoxic cembranoid diterpenes from a soft coral Sinularia gibberosa. J Nat Prod. 68:649–652. 2005. View Article : Google Scholar : PubMed/NCBI

6 

Yang B, Zhou XF, Lin XP, Liu J, Peng Y, Yang XW and Liu YH: Cembrane diterpenes chemistry and biological properties. Curr Org Chem. 16:1512–1539. 2012. View Article : Google Scholar

7 

Chao CH, Chou KJ, Huang CY, Wen ZH, Hsu CH, Wu YC, Dai CF and Sheu JH: Bioactive cembranoids from the soft coral Sinularia crassa. Mar Drugs. 9:1955–1968. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Li Y, Gao AH, Huang H, Li J, Mollo E, Gavagnin M, Cimino G, Gu YC and Guo YW: Diterpenoids from the hainan soft coral sinularia parva. Helvetica Chim Acta. 92:1341–1348. 2009. View Article : Google Scholar

9 

Coll JC, Price IR, Konig GM and Bowden BF: Algal overgrowth of alcyonacean soft corals. Mar Biol. 96:129–135. 1987. View Article : Google Scholar

10 

Lu Y, Huang CY, Lin YF, Wen ZH, Su JH, Kuo YH, Chiang MY and Sheu JH: Anti-inflammatory cembranoids from the soft corals Sinularia querciformis and Sinularia granosa. J Nat Prod. 71:1754–1759. 2008. View Article : Google Scholar : PubMed/NCBI

11 

Lu Y, Su JH, Huang CY, Liu YC, Kuo YH, Wen ZH, Hsu CH and Sheu JH: Cembranoids from the soft corals Sinularia granosa and Sinularia querciformis. Chem Pharm Bull (Tokyo). 58:464–466. 2010. View Article : Google Scholar : PubMed/NCBI

12 

Liu CI, Chen CC, Chen JC, Su JH, Huang HH, Chen JY and Wu YJ: Proteomic analysis of anti-tumor effects of 11-dehydrosinulariolide on CAL-27 cells. Mar Drugs. 9:1254–1272. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Lin YS, Chen CH, Liaw CC, Chen YC, Kuo YH and Shen YC: Cembrane diterpenoids from the Taiwanese soft coral Sinularia flexibilis. Tetrahedron. 65:9157–9164. 2009. View Article : Google Scholar

14 

Aceret TL, Coll JC, Uchio Y and Sammarco PW: Antimicrobial activity of the diterpenes flexibilide and sinulariolide derived from Sinularia flexibilis Quoy and Gaimard 1833 (Coelenterata: Alcyonacea, Octocorallia). Comp Biochem Physiol C Pharmacol Toxicol Endocrinol. 120:121–126. 1998. View Article : Google Scholar : PubMed/NCBI

15 

Wu YJ, Neoh CA, Tsao CY, Su JH and Li HH: Sinulariolide suppresses human hepatocellular carcinoma cell migration and invasion by inhibiting matrix metalloproteinase-2/-9 through MAPKs and PI3K/Akt signaling pathways. Int J Mol Sci. 16:16469–16482. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Chen YJ, Su JH, Tsao CY, Hung CT, Chao HH, Lin JJ, Liao MH, Yang ZY, Huang HH, Tsai FJ, et al: Sinulariolide induced hepatocellular carcinoma apoptosis through activation of mitochondrial-related apoptotic and PERK/eIF2α/ATF4/CHOP pathway. Molecules. 18:10146–10161. 2013. View Article : Google Scholar : PubMed/NCBI

17 

Li HH, Su JH, Chiu CC, Lin JJ, Yang ZY, Hwang WI, Chen YK, Lo YH and Wu YJ: Proteomic investigation of the sinulariolide-treated melanoma cells A375: Effects on the cell apoptosis through mitochondrial-related pathway and activation of caspase cascade. Mar Drugs. 11:2625–2642. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Neoh CA, Wang RY, Din ZH, Su JH, Chen YK, Tsai FJ, Weng SH and Wu YJ: Induction of apoptosis by sinulariolide from soft coral through mitochondrial-related and p38MAPK pathways on human bladder carcinoma cells. Mar Drugs. 10:2893–2911. 2012. View Article : Google Scholar : PubMed/NCBI

19 

Li S, Lin YC, Ho CT, Lin PY, Suzawa M, Wang HC, Chu CL, Chen DY and Lin CC: Formulated extract from multiple citrus peels impairs dendritic cell functions and attenuates allergic contact hypersensitivity. Int Immunopharmacol. 20:12–23. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Hsieh PW, Chang FR, McPhail AT, Lee KH and Wu YC: New cembranolide analogues from the formosan soft coral Sinularia flexibilis and their cytotoxicity. Nat Prod Res. 17:409–418. 2003. View Article : Google Scholar : PubMed/NCBI

21 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

22 

Lin CC, Chu CL, Ng CS, Lin CY, Chen DY, Pan IH and Huang KJ: Immunomodulation of phloretin by impairing dendritic cell activation and function. Food Funct. 5:997–1006. 2014. View Article : Google Scholar : PubMed/NCBI

23 

Caux C, Massacrier C, Vanbervliet B, Dubois B, Van Kooten C, Durand I and Banchereau J: Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 180:1263–1272. 1994. View Article : Google Scholar : PubMed/NCBI

24 

Pinchuk LM, Polacino PS, Agy MB, Klaus SJ and Clark EA: The role of CD40 and CD80 accessory cell molecules in dendritic cell-dependent HIV-1 infection. Immunity. 1:317–325. 1994. View Article : Google Scholar : PubMed/NCBI

25 

Diehl S and Rincón M: The two faces of IL-6 on Th1/Th2 differentiation. Mol Immunol. 39:531–536. 2002. View Article : Google Scholar : PubMed/NCBI

26 

Heufler C, Koch F, Stanzl U, Topar G, Wysocka M, Trinchieri G, Enk A, Steinman RM, Romani N and Schuler G: Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-gamma production by T helper 1 cells. Eur J Immunol. 26:659–668. 1996. View Article : Google Scholar : PubMed/NCBI

27 

Moncada S, Palmer RM and Higgs EA: Nitric oxide: Physiology, pathophysiology, and pharmacology. Pharmacol Rev. 43:109–142. 1991.PubMed/NCBI

28 

Bonham CA, Lu L, Li Y, Hoffman RA, Simmons RL and Thomson AW: Nitric oxide production by mouse bone marrow-derived dendritic cells: Implications for the regulation of allogeneic T cell responses. Transplantation. 62:1871–1877. 1996. View Article : Google Scholar : PubMed/NCBI

29 

Lu L, Bonham CA, Chambers FG, Watkins SC, Hoffman RA, Simmons RL and Thomson AW: Induction of nitric oxide synthase in mouse dendritic cells by IFN-gamma, endotoxin, and interaction with allogenic T cells: Nitric oxide production is associated with dendritic cell apoptosis. J Immunol. 157:3577–3586. 1996.PubMed/NCBI

30 

Neves BM, Cruz MT, Francisco V, Garcia-Rodriguez C, Silvestre R, Cordeiro-da-Silva A, Dinis AM, Batista MT, Duarte CB and Lopes MC: Differential roles of PI3-kinase, MAPKs and NF-kappaB on the manipulation of dendritic cell T(h)1/T(h)2 cytokine/chemokine polarizing profile. Mol Immunol. 46:2481–2492. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Rescigno M, Martino M, Sutherland CL, Gold MR and Ricciardi-Castagnoli P: Dendritic cell survival and maturation are regulated by different signaling pathways. J Exp Med. 188:2175–2180. 1998. View Article : Google Scholar : PubMed/NCBI

32 

Ardeshna KM, Pizzey AR, Devereux S and Khwaja A: The PI3 kinase, p38 SAP kinase, and NF-kappaB signal transduction pathways are involved in the survival and maturation of lipopolysaccharide-stimulated human monocyte-derived dendritic cells. Blood. 96:1039–1046. 2000.PubMed/NCBI

33 

Xie J, Qian J, Yang J, Wang S, Freeman ME III and Yi Q: Critical roles of Raf/MEK/ERK and PI3K/AKT signaling and inactivation of p38 MAP kinase in the differentiation and survival of monocyte-derived immature dendritic cells. Exp Hematol. 33:564–572. 2005. View Article : Google Scholar : PubMed/NCBI

34 

Hsiao KY, Wu YJ, Liu ZN, Chuang CW, Huang HH and Kuo SM: Anticancer effects of sinulariolide-conjugated hyaluronan nanoparticles on lung adenocarcinoma cells. Molecules. 21:2972016. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Chung TW, Li YR, Huang W, Su JH, Chan HL, Lin SH, Liu CS, Lin SC, Lin CC, Lin CH, Lin CH, et al: Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells. Mol Med Rep 16: 6992-7000, 2017.
APA
Chung, T., Li, Y., Huang, W., Su, J., Chan, H., Lin, S. ... Lin, C. (2017). Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells. Molecular Medicine Reports, 16, 6992-7000. https://doi.org/10.3892/mmr.2017.7480
MLA
Chung, T., Li, Y., Huang, W., Su, J., Chan, H., Lin, S., Liu, C., Lin, S., Lin, C., Lin, C."Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells". Molecular Medicine Reports 16.5 (2017): 6992-7000.
Chicago
Chung, T., Li, Y., Huang, W., Su, J., Chan, H., Lin, S., Liu, C., Lin, S., Lin, C., Lin, C."Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells". Molecular Medicine Reports 16, no. 5 (2017): 6992-7000. https://doi.org/10.3892/mmr.2017.7480
Copy and paste a formatted citation
x
Spandidos Publications style
Chung TW, Li YR, Huang W, Su JH, Chan HL, Lin SH, Liu CS, Lin SC, Lin CC, Lin CH, Lin CH, et al: Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells. Mol Med Rep 16: 6992-7000, 2017.
APA
Chung, T., Li, Y., Huang, W., Su, J., Chan, H., Lin, S. ... Lin, C. (2017). Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells. Molecular Medicine Reports, 16, 6992-7000. https://doi.org/10.3892/mmr.2017.7480
MLA
Chung, T., Li, Y., Huang, W., Su, J., Chan, H., Lin, S., Liu, C., Lin, S., Lin, C., Lin, C."Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells". Molecular Medicine Reports 16.5 (2017): 6992-7000.
Chicago
Chung, T., Li, Y., Huang, W., Su, J., Chan, H., Lin, S., Liu, C., Lin, S., Lin, C., Lin, C."Sinulariolide suppresses LPS‑induced phenotypic and functional maturation of dendritic cells". Molecular Medicine Reports 16, no. 5 (2017): 6992-7000. https://doi.org/10.3892/mmr.2017.7480
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