The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
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Beauvericin, a cyclic peptide, inhibits inflammatory responses in macrophages by inhibiting the NF-κB pathway

  • Yoo, Sulgi (Department of Genetic Engineering, Sungkyunkwan University) ;
  • Kim, Mi-Yeon (School of Systems Biomedical Science, Soongsil University) ;
  • Cho, Jae Youl (Department of Genetic Engineering, Sungkyunkwan University)
  • Received : 2017.01.11
  • Accepted : 2017.04.28
  • Published : 2017.07.01
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Abstract

Beauvericin (BEA), a cyclic hexadepsipeptide produced by the fungus Beauveria bassiana, is known to have anti-cancer, anti-inflammatory, and anti-microbial actions. However, how BEA suppresses macrophage-induced inflammatory responses has not been fully elucidated. In this study, we explored the anti-inflammatory properties of BEA and the underlying molecular mechanisms using lipopolysaccharide (LPS)-treated macrophage-like RAW264.7 cells. Levels of nitric oxide (NO), mRNA levels of transcription factors and the inflammatory genes inducible NO synthase (iNOS) and interleukin (IL)-1, and protein levels of activated intracellular signaling molecules were determined by Griess assay, semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), luciferase reporter gene assay, and immunoblotting analysis. BEA dose-dependently blocked the production of NO in LPS-treated RAW264.7 cells without inducing cell cytotoxicity. BEA also prevented LPS-triggered morphological changes. This compound significantly inhibited nuclear translocation of the $NF-{\kappa}B$ subunits p65 and p50. Luciferase reporter gene assays demonstrated that BEA suppresses MyD88-dependent NF-${\kappa}B$ activation. By analyzing upstream signaling events for $NF-{\kappa}B$ activation and overexpressing Src and Syk, these two enzymes were revealed to be targets of BEA. Together, these results suggest that BEA suppresses $NF-{\kappa}B$-dependent inflammatory responses by suppressing both Src and Syk.

Keywords

References

  1. Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085-2088. https://doi.org/10.1126/science.282.5396.2085
  2. Takeda K, Akira S. TLR signaling pathways. Semin Immunol. 2004;16:3-9. https://doi.org/10.1016/j.smim.2003.10.003
  3. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805-820. https://doi.org/10.1016/j.cell.2010.01.022
  4. Yi YS, Son YJ, Ryou C, Sung GH, Kim JH, Cho JY. Functional roles of Syk in macrophage-mediated inflammatory responses. Mediators Inflamm. 2014. doi: 10.1155/2014/270302.
  5. Ohtsubo M, Okazaki H, Nishimoto T. The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA. J Cell Biol. 1989;109:1389-1397. https://doi.org/10.1083/jcb.109.4.1389
  6. Takada Y, Mukhopadhyay A, Kundu GC, Mahabeleshwar GH, Singh S, Aggarwal BB. Hydrogen peroxide activates NF-kappa B through tyrosine phosphorylation of I kappa B alpha and serine phosphorylation of p65: evidence for the involvement of I kappa B alpha kinase and Syk protein-tyrosine kinase. J Biol Chem. 2003;278:24233-24241. https://doi.org/10.1074/jbc.M212389200
  7. Yang Y, Lee J, Rhee MH, Yu T, Baek KS, Sung NY, Kim Y, Yoon K, Kim JH, Kwak YS, Hong S, Kim JH, Cho JY. Molecular mechanism of protopanaxadiol saponin fraction-mediated anti-inflammatory actions. J Ginseng Res. 2015;39:61-68. https://doi.org/10.1016/j.jgr.2014.06.002
  8. Coussens LM, Werb Z. Inflammation and cancer. Nature. 2002;420:860-867. https://doi.org/10.1038/nature01322
  9. Jeon J, Kim Y, Kim H, Kang JS, Lee WJ. Anti-inflammatory effect of alloferon on ovalbumin-induced asthma. Immune Netw. 2015;15:304-312. https://doi.org/10.4110/in.2015.15.6.304
  10. Morgan MJ, Kim YS. The serine threonine kinase RIP3: lost and found. BMB Rep. 2015;48:303-312. https://doi.org/10.5483/BMBRep.2015.48.6.068
  11. Logrieco A, Moretti A, Castella G, Kostecki M, Golinski P, Ritieni A, Chelkowski J. Beauvericin production by Fusarium species. Appl Environ Microbiol. 1998;64:3084-3088.
  12. Ovchinnikov YA, Ivanov VT, Mikhaleva II. The synthesis and some properties of beauvericin. Tetrahedron Lett. 1971;(2):159-162.
  13. Grove JF, Pople M. The insecticidal activity of beauvericin and the enniatin complex. Mycopathologia. 1980;70:103-105. https://doi.org/10.1007/BF00443075
  14. Fornelli F, Minervini F, Logrieco A. Cytotoxicity of fungal metabolites to lepidopteran (Spodoptera frugiperda) cell line (SF-9). J Invertebr Pathol. 2004;85:74-79. https://doi.org/10.1016/j.jip.2004.01.002
  15. Castlebury L, Sutherland J, Tanner L, Henderson A, Cerniglia C. Use of a bioassay to evaluate the toxicity of beauvericin to bacteria. World J Microbiol Biotechnol. 1999;15:119-121. https://doi.org/10.1023/A:1008895421989
  16. Wang Q, Xu L. Beauvericin, a bioactive compound produced by fungi: a short review. Molecules. 2012;17:2367-2377. https://doi.org/10.3390/molecules17032367
  17. Zhan J, Burns AM, Liu MX, Faeth SH, Gunatilaka AA. Search for cell motility and angiogenesis inhibitors with potential anticancer activity: beauvericin and other constituents of two endophytic strains of Fusarium oxysporum. J Nat Prod. 2007;70:227-232. https://doi.org/10.1021/np060394t
  18. Wu XF, Xu R, Ouyang ZJ, Qian C, Shen Y, Wu XD, Gu YH, Xu Q, Sun Y. Beauvericin ameliorates experimental colitis by inhibiting activated T cells via downregulation of the PI3K/Akt signaling pathway. PLoS One. 2013;8:e83013. https://doi.org/10.1371/journal.pone.0083013
  19. Watjen W, Debbab A, Hohlfeld A, Chovolou Y, Proksch P. The mycotoxin beauvericin induces apoptotic cell death in H4IIE hepatoma cells accompanied by an inhibition of $NF-{\kappa}B$-activity and modulation of MAP-kinases. Toxicol Lett. 2014;231:9-16. https://doi.org/10.1016/j.toxlet.2014.08.021
  20. Baek KS, Yi YS, Son YJ, Yoo S, Sung NY, Kim Y, Hong S, Aravinthan A, Kim JH, Cho JY. In vitro and in vivo anti-inflammatory activities of Korean Red Ginseng-derived components. J Ginseng Res. 2016;40:437-444. https://doi.org/10.1016/j.jgr.2016.08.003
  21. Cho JY, Baik KU, Jung JH, Park MH. In vitro anti-inflammatory effects of cynaropicrin, a sesquiterpene lactone, from Saussurea lappa. Eur J Pharmacol. 2000;398:399-407. https://doi.org/10.1016/S0014-2999(00)00337-X
  22. Jung YY, Hong JT, Han SB, Park YH, Son DJ. Effect of Ixeris dentata Nakai extract on nitric oxide production and prostaglandin E2 generation in LPS-stimulated RAW264.7 Cells. Immune Netw. 2015;15:325-330. https://doi.org/10.4110/in.2015.15.6.325
  23. Schrader M, Bahlmann K, Giese G, Hell SW. 4Pi-confocal imaging in fixed biological specimens. Biophys J. 1998;75:1659-1668. https://doi.org/10.1016/S0006-3495(98)77608-8
  24. Latt SA, Stetten G. Spectral studies on 33258 Hoechst and related bisbenzimidazole dyes useful for fluorescent detection of deoxyribonucleic acid synthesis. J Histochem Cytochem. 1976;24:24-33. https://doi.org/10.1177/24.1.943439
  25. Jeon HJ, You SY, Park YS, Chang JW, Kim JS, Oh JS. TCTP regulates spindle microtubule dynamics by stabilizing polar microtubules during mouse oocyte meiosis. Biochim Biophys Acta. 2016;1863:630-637. https://doi.org/10.1016/j.bbamcr.2016.01.012
  26. Gerlier D, Thomasset N. Use of MTT colorimetric assay to measure cell activation. J Immunol Methods. 1986;94:57-63. https://doi.org/10.1016/0022-1759(86)90215-2
  27. Kim JH, Kim MY, Kim JH, Cho JY. Fisetin suppresses macrophagemediated inf lammatory responses by blockade of Src and Syk. Biomol Ther (Seoul). 2015;23:414-420. https://doi.org/10.4062/biomolther.2015.036
  28. Kim MS, Lee Y, Sung GH, Kim JH, Park JG, Kim HG, Baek KS, Cho JH, Han J, Lee KH, Hong S, Kim JH, Cho JY. Pro-apoptotic activity of 4-isopropyl-2-(1-phenylethyl) aniline isolated from Cordyceps bassiana. Biomol Ther (Seoul). 2015;23:367-373. https://doi.org/10.4062/biomolther.2015.021
  29. Bak MJ, Truong VL, Ko SY, Nguyen XN, Jun M, Hong SG, Lee JW, Jeong WS. Induction of Nrf2/ARE-mediated cytoprotective genes by red ginseng oil through ASK1-MKK4/7-JNK and p38 MAPK signaling pathways in HepG2 cells. J Ginseng Res. 2016;40:423-430. https://doi.org/10.1016/j.jgr.2016.07.003
  30. Jung KK, Lee HS, Cho JY, Shin WC, Rhee MH, Kim TG, Kang JH, Kim SH, Hong S, Kang SY. Inhibitory effect of curcumin on nitric oxide production from lipopolysaccharide-activated primary microglia. Life Sci. 2006;79:2022-2031. https://doi.org/10.1016/j.lfs.2006.06.048
  31. Yu T, Ahn HM, Shen T, Yoon K, Jang HJ, Lee YJ, Yang HM, Kim JH, Kim C, Han MH, Cha SH, Kim TW, Kim SY, Lee J, Cho JY. Antiinflammatory activity of ethanol extract derived from Phaseolus angularis beans. J Ethnopharmacol. 2011;137:1197-1206. https://doi.org/10.1016/j.jep.2011.07.048
  32. Byeon SE, Lee YG, Kim BH, Shen T, Lee SY, Park HJ, Park SC, Rhee MH, Cho JY. Surfactin blocks NO production in lipopolysaccharideactivated macrophages by inhibiting NF-kappaB activation. J Microbiol Biotechnol. 2008;18:1984-1989.
  33. Cho JY, Choi GJ, Son SW, Jang KS, Lim HK, Lee SO, Sung ND, Cho KY, Kim JC. Isolation and antifungal activity of lignans from Myristica fragrans against various plant pathogenic fungi. Pest Manag Sci. 2007;63:935-940. https://doi.org/10.1002/ps.1420
  34. Sung NY, Kim MY, Cho JY. Scutellarein reduces inflammatory responses by inhibiting Src kinase activity. Korean J Physiol Pharmacol. 2015;19:441-449. https://doi.org/10.4196/kjpp.2015.19.5.441
  35. Yang WS, Ratan ZA, Kim G, Lee Y, Kim MY, Kim JH, Cho JY. 4-Isopropyl-2,6-bis(1-phenylethyl)aniline 1, an analogue of KTH-13 isolated from Cordyceps bassiana , inhibits the $NF-{\kappa}B$ mediated inflammatory response. Mediators Inflamm. 2015. doi:10.1155/2015/143025.
  36. Baek KS, Hong YD, Kim Y, Sung NY, Yang S, Lee KM, Park JY, Park JS, Rho HS, Shin SS, Cho JY. Anti-inflammatory activity of AP-SF, a ginsenoside-enriched fraction, from Korean ginseng. J Ginseng Res. 2015;39:155-161. https://doi.org/10.1016/j.jgr.2014.10.004
  37. Kim S, Oh MH, Kim BS, Kim WI, Cho HS, Park BY, Park C, Shin GW, Kwon J. Upregulation of heme oxygenase-1 by ginsenoside Ro attenuates lipopolysaccharide-induced inflammation in macrophage cells. J Ginseng Res. 2015;39:365-370. https://doi.org/10.1016/j.jgr.2015.03.008
  38. Hossen MJ, Jeon SH, Kim SC, Kim JH, Jeong D, Sung NY, Yang S, Baek KS, Kim JH, Yoon DH, Song WO, Yoon KD, Cho SH, Lee S, Kim JH, Cho JY. In vitro and in vivo anti-inflammatory activity of Phyllanthus acidus methanolic extract. J Ethnopharmacol. 2015;168:217-228. https://doi.org/10.1016/j.jep.2015.03.043
  39. Hoesel B, Schmid JA. The complexity of $NF-{\kappa}B$ signaling in inflammation and cancer. Mol Cancer. 2013;12:86. https://doi.org/10.1186/1476-4598-12-86
  40. Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1:a001651.
  41. Caamano J, Hunter CA. NF-kappaB family of transcription factors: central regulators of innate and adaptive immune functions. Clin Microbiol Rev. 2002;15:414-429. https://doi.org/10.1128/CMR.15.3.414-429.2002
  42. Lee YG, Chain BM, Cho JY. Distinct role of spleen tyrosine kinase in the early phosphorylation of inhibitor of kappaB alpha via activation of the phosphoinositide-3-kinase and Akt pathways. Int J Biochem Cell Biol. 2009;41:811-821. https://doi.org/10.1016/j.biocel.2008.08.011
  43. Lee JY, Lee YG, Lee J, Yang KJ, Kim AR, Kim JY, Won MH, Park J, Yoo BC, Kim S, Cho WJ, Cho JY. Akt Cys-310-targeted inhibition by hydroxylated benzene derivatives is tightly linked to their immunosuppressive effects. J Biol Chem. 2010;285:9932-9948. https://doi.org/10.1074/jbc.M109.074872
  44. Murphy M, Xiong Y, Pattabiraman G, Qiu F, Medvedev AE. Pellino-1 positively regulates toll-like receptor (TLR) 2 and TLR4 signaling and is suppressed upon induction of endotoxin tolerance. J Biol Chem. 2015;290:19218-19232. https://doi.org/10.1074/jbc.M115.640128
  45. Chaudhary A, Fresquez TM, Naranjo MJ. Tyrosine kinase Syk associates with toll-like receptor 4 and regulates signaling in human monocytic cells. Immunol Cell Biol. 2007;85:249-256. https://doi.org/10.1038/sj.icb7100030
  46. Ko R, Lee SY. Glycogen synthase kinase $3{\beta}$ in Toll-like receptor signaling. BMB Rep. 2016;49:305-310. https://doi.org/10.5483/BMBRep.2016.49.6.059

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