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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Anti-inflammatory effects of a novel compound, MPQP, through the inhibition of IRAK1 signaling pathways in LPS-stimulated RAW 264.7 macrophages

  • Received : 2018.03.28
  • Accepted : 2018.05.23
  • Published : 2018.06.30
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Abstract

Small-molecule inhibitors are widely used to treat a variety of inflammatory diseases. In this study, we found a novel anti-inflammatory compound, 1-[(2R,4S)-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-1-yl]prop-2-en-1-one (MPQP). It showed strong anti-inflammatory effects in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. These effects were exerted through the inhibition of the production of NO and pro-inflammatory cytokines, such as interleukin (IL)-6, $IL-1{\beta}$, and tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$). Furthermore, MPQP decreased the expression levels of inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2). Additionally, it mediated the inhibition of the phosphorylation of p38, c-Jun N-terminal kinase (JNK), the inhibitor of ${\kappa}B{\alpha}$ ($I{\kappa}B{\alpha}$), and their upstream kinases, $I{\kappa}B$ kinase (IKK) ${\alpha}/{\beta}$, mitogen-activated protein kinase kinase (MKK) 3/6, and MKK4. Furthermore, the expression of IL-1 receptor-associated kinase 1 (IRAK1) that regulates $NF-{\kappa}B$, p38, and the JNK signaling pathways, was also increased by MPQP. These results indicate that MPQP regulates the IRAK1-mediated inflammatory signaling pathways by targeting IRAK1 or its upstream factors.

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References

  1. Kim E, Yang WS, Kim JH et al (2014) Lancemaside A from Codonopsis lanceolata modulates the inflammatory responses mediated by monocytes and macrophages. Mediators Inflamm 2014, 405158-405158
  2. Nowarski R, Gagliani N, Huber S and Flavell RA (2013) Innate immune cells in inflammation and cancer. Cancer Immunol Res 1, 77-84 https://doi.org/10.1158/2326-6066.CIR-13-0081
  3. Wu LC, Fan NC, Lin MH et al (2008) Anti- inflammatory effect of spilanthol from Spilanthes acmella on murine macrophage by down-regulating LPS-induced inflammatory mediators. J Agric Food Chem 56, 2341-2349 https://doi.org/10.1021/jf073057e
  4. Libby P (2007) Inflammatory mechanisms: the molecular basis of inflammation and disease. Nutr Rev 65, S140-S146 https://doi.org/10.1301/nr.2007.dec.S140-S146
  5. Barton GM and Medzhitov R (2003) Toll-like receptor signaling pathways. Science 300, 1524-1525 https://doi.org/10.1126/science.1085536
  6. Ordureau A, Smith H, Windheim M et al (2008) The IRAK-catalysed activation of the E3 ligase function of Pellino isoforms induces the Lys63-linked polyubiquitination of IRAK1. Biochem J 409, 43-52 https://doi.org/10.1042/BJ20071365
  7. Avila M and Gonzalez-Espinosa C (2011) Signaling through Toll-like receptor 4 and mast cell-dependent innate immunity responses. IUBMB Life 63, 873-880 https://doi.org/10.1002/iub.555
  8. Jiang Z, Ninomiya-Tsuji J, Qian Y, Matsumoto K and Li X (2002) Interleukin-1 (IL-1) receptor-associated kinasedependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. Mol Cell Biol 22, 7158-7167 https://doi.org/10.1128/MCB.22.20.7158-7167.2002
  9. Schreiber SL (1998) Chemical genetics resulting from a passion for synthetic organic chemistry. Biorg Med Chem 6, 1127-1152 https://doi.org/10.1016/S0968-0896(98)00126-6
  10. Thompson LA and Ellman JA (1996) Synthesis and applications of small molecule libraries. Chem Rev 96, 555-600 https://doi.org/10.1021/cr9402081
  11. Chen W, Wang J, Luo Y et al (2016) Ginsenoside Rb1 and compound K improve insulin signaling and inhibit ER stress-associated NLRP3 inflammasome activation in adipose tissue. J Ginseng Res 40, 351-358 https://doi.org/10.1016/j.jgr.2015.11.002
  12. Cha BJ, Park JH, Shrestha S et al (2015) Glycosyl glycerides from hydroponic Panax ginseng inhibited NO production in lipopolysaccharide-stimulated RAW264. 7 cells. J Ginseng Res 39, 162-168 https://doi.org/10.1016/j.jgr.2014.10.005
  13. Cho YC., Kim YR, Kim BR and Cho S (2016) Thunbergia alata inhibits inflammatory responses through the inactivation of ERK and STAT3 in macrophages. Int J Mol Med 38, 1596-1604 https://doi.org/10.3892/ijmm.2016.2746
  14. Funk CD (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Sci 294, 1871-1875 https://doi.org/10.1126/science.294.5548.1871
  15. Feghali CA and Wright TM (1997) Cytokines in acute and chronic inflammation. Front Biosci 2, d12-d26
  16. Ma P, Liu HT., Wei P et al (2011) Chitosan oligosaccharides inhibit LPS-induced over-expression of IL-6 and TNF-${\alpha}$ in RAW264. 7 macrophage cells through blockade of mitogen-activated protein kinase (MAPK) and PI3K/Akt signaling pathways. Carbohydr Polym 84, 1391-1398 https://doi.org/10.1016/j.carbpol.2011.01.045
  17. Kwak HJ, Song JS, Heo JY, Yang SD, Nam JY and Cheon HG (2005) Roflumilast inhibits lipopolysaccharideinduced inflammatory mediators via suppression of nuclear factor-${\kappa}B$, p38 mitogen-activated protein kinase, and c-Jun NH2-terminal kinase activation. J Pharmacol Exp Ther 315, 1188-1195 https://doi.org/10.1124/jpet.105.092056
  18. Lee J, Tae N, Lee JJ, Kim T and Lee JH (2010) Eupatolide inhibits lipopolysaccharide-induced COX-2 and iNOS expression in RAW264. 7 cells by inducing proteasomal degradation of TRAF6. Eur J Pharmacol 636, 173-180 https://doi.org/10.1016/j.ejphar.2010.03.021
  19. Finco TS, Beg AA and Baldwin AS (1994) Inducible phosphorylation of I kappa B alpha is not sufficient for its dissociation from NF-kappa B and is inhibited by protease inhibitors. Proc Natl Acad Sci U S A 91, 11884-11888 https://doi.org/10.1073/pnas.91.25.11884
  20. Karin M, Liu Zg and Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9, 240-246 https://doi.org/10.1016/S0955-0674(97)80068-3
  21. Plotnikov A, Zehorai E, Procaccia S and Seger R (2011) The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta 1813, 1619-1633 https://doi.org/10.1016/j.bbamcr.2010.12.012
  22. Neu HC (1992) Quinolone antimicrobial agents. Annu Rev Med 43, 465-486 https://doi.org/10.1146/annurev.me.43.020192.002341
  23. Abadi AH, Hegazy GH and El-Zaher AA (2005) Synthesis of novel 4-substituted-7-trifluoromethylquinoline derivatives with nitric oxide releasing properties and their evaluation as analgesic and anti-inflammatory agents. Biorg Med Chem 13, 5759-5765 https://doi.org/10.1016/j.bmc.2005.05.053
  24. Solomon VR and Lee H (2011) Quinoline as a privileged scaffold in cancer drug discovery. Curr Med Chem 18, 1488-1508 https://doi.org/10.2174/092986711795328382
  25. Kumar S, Bawa S and Gupta H (2009) Biological activities of quinoline derivatives. Mini Rev Med Chem 9, 1648-1654 https://doi.org/10.2174/138955709791012247
  26. Dinarello CA (2010) Anti-inflammatory agents: present and future. Cell 140, 935-950 https://doi.org/10.1016/j.cell.2010.02.043
  27. Palladino MA, Bahjat FR, Theodorakis EA and Moldawer LL (2003) Anti-TNF-${\alpha}$ therapies: the next generation. Nature Reviews Drug Discovery 2, 736-742 https://doi.org/10.1038/nrd1175
  28. Kim SJ, Cha JY, Kang HS et al (2016) Corosolic acid ameliorates acute inflammation through inhibition of IRAK-1 phosphorylation in macrophages. BMB Rep 49, 276-281 https://doi.org/10.5483/BMBRep.2016.49.5.241
  29. Li M, Yu D, Ni B and Hao F (2017) Interleukin-1 receptor associated kinase 1 is a potential therapeutic target of anti-inflammatory therapy for systemic lupus erythematosus. Mol Immunol 87, 94-101 https://doi.org/10.1016/j.molimm.2017.03.018
  30. Nishimoto N (2006) Interleukin-6 in rheumatoid arthritis. Curr Opin Rheumatol 18, 277-281 https://doi.org/10.1097/01.bor.0000218949.19860.d1
  31. Anestakis D, Petanidis S, Kalyvas S et al (2015) Mechanisms and applications of interleukins in cancer immunotherapy. Int J Mol Sci 16, 1691-1710 https://doi.org/10.3390/ijms16011691
  32. Scheidt-Nave C, Bismar H, Leidig-Bruckner G et al (2001) Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause. J Clin Endocrinol Metab 86, 2032-2042
  33. Smolen JS and Maini RN (2006) Interleukin-6: a new therapeutic target. Arthrit Res Ther 8, S5 https://doi.org/10.1186/ar1969
  34. Emery P, Keystone E, Tony H et al (2008) IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 67, 1516-1523 https://doi.org/10.1136/ard.2008.092932