N-(p-Coumaryol)-Tryptamine Suppresses the Activation of JNK/c-Jun Signaling Pathway in LPS-Challenged RAW264.7 Cells

  • Vo, Van Anh (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Lee, Jae-Won (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Park, Jun-Ho (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Kwon, Jae-Hyun (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Lee, Hee Jae (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Kim, Sung-Soo (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Kwon, Yong-Soo (Department of Pharmacology, College of Pharmacy, Kangwon National University) ;
  • Chun, Wanjoo (Department of Pharmacology, College of Medicine, Kangwon National University)
  • Received : 2014.02.03
  • Accepted : 2014.03.24
  • Published : 2014.05.31


N-(p-Coumaryol) tryptamine (CT), a phenolic amide, has been reported to exhibit anti-oxidant and anti-inflammatory activities. However, the underlying mechanism by which CT exerts its pharmacological properties has not been clearly demonstrated. The objective of this study is to elucidate the anti-inflammatory mechanism of CT in lipopolysaccharide (LPS)-challenged RAW264.7 macrophage cells. CT significantly inhibited LPS-induced extracellular secretion of pro-inflammatory mediators such as nitric oxide (NO) and $PGE_2$, and protein expressions of iNOS and COX-2. In addition, CT significantly suppressed LPS-induced secretion of pro-inflammatory cytokines such as TNF-${\alpha}$ and IL-$1{\beta}$. To elucidate the underlying anti-inflammatory mechanism of CT, involvement of MAPK and Akt signaling pathways was examined. CT significantly attenuated LPS-induced activation of JNK/c-Jun, but not ERK and p38, in a concentration-dependent manner. Interestingly, CT appeared to suppress LPS-induced Akt phosphorylation. However, JNK inhibition, but not Akt inhibition, resulted in the suppression of LPS-induced responses, suggesting that JNK/c-Jun signaling pathway significantly contributes to LPS-induced inflammatory responses and that LPS-induced Akt phosphorylation might be a compensatory response to a stress condition. Taken together, the present study clearly demonstrates CT exerts anti-inflammatory activity through the suppression of JNK/c-Jun signaling pathway in LPS-challenged RAW264.7 macrophage cells.



  1. Andrianaivoravelona, J. O., Terreaux, C., Sahpaz, S., Rasolondramanitra, J. and Hostettmann, K. (1999) A phenolic glycoside and N- (p-coumaroyl)-tryptamine from Ravensara anisata. Phytochemistry 52, 1145-1148.
  2. Cho, S. G. and Choi, E. J. (2002) Apoptotic signaling pathways: caspases and stress-activated protein kinases. J. Biochem. Mol. Biol. 35, 24-27.
  3. Dilshara, M. G., Jayasooriya, R. G., Lee, S., Jeong, J. B., Seo, Y. T., Choi, Y. H., Jeong, J. W., Jang, Y. P., Jeong, Y. K. and Kim, G. Y. (2013) Water extract of processed Hydrangea macrophylla (Thunb.) Ser. leaf attenuates the expression of pro-inflammatory mediators by suppressing Akt-mediated NF-kappaB activation. Environ. Toxicol. Pharmacol. 35, 311-319.
  4. Guha, M. and Mackman, N. (2001) LPS induction of gene expression in human monocytes. Cell Signal. 13, 85-94.
  5. Ha, Y. M., Ham, S. A., Kim, Y. M., Lee, Y. S., Kim, H. J., Seo, H. G., Lee, J. H., Park, M. K. and Chang, K. C. (2011) beta(1)-adrenergic receptor-mediated HO-1 induction, via PI3K and p38 MAPK, by isoproterenol in RAW 264.7 cells leads to inhibition of HMGB1 release in LPS-activated RAW 264.7 cells and increases in survival rate of CLP-induced septic mice. Biochem. Pharmacol. 82, 769-777.
  6. Ip, Y. T. and Davis, R. J. (1998) Signal transduction by the c-Jun Nterminal kinase (JNK)--from inflammation to development. Curr. Opin. Cell Biol. 10, 205-219.
  7. Itharat, A. and Hiransai, P. (2012) Dioscoreanone suppresses LPSinduced nitric oxide production and inflammatory cytokine expression in RAW 264.7 macrophages by NF-kappaB and ERK1/2 signaling transduction. J. Cell. Biochem. 113, 3427-3435.
  8. Joh, E. H. and Kim, D. H. (2011) Kalopanaxsaponin A ameliorates experimental colitis in mice by inhibiting IRAK-1 activation in the NFkappaB and MAPK pathways. Br. J. Pharmacol. 162, 1731-1742.
  9. Kidd, L. B., Schabbauer, G. A., Luyendyk, J. P., Holscher, T. D., Tilley, R. E., Tencati, M. and Mackman, N. (2008) Insulin activation of the phosphatidylinositol 3-kinase/protein kinase B (Akt) pathway reduces lipopolysaccharide-induced inflammation in mice. J. Pharmacol. Exp. Ther. 326, 348-353.
  10. Kim, Y. J., Shin, Y., Lee, K. H. and Kim, T. J. (2012) Anethum graveloens flower extracts inhibited a lipopolysaccharide-induced inflammatory response by blocking iNOS expression and NF-kappaB activity in macrophages. Biosci. Biotechnol. Biochem. 76, 1122-1127.
  11. Lee, J. W., Bae, C. J., Choi, Y. J., Kim, S. I., Kim, N. H., Lee, H. J., Kim, S. S., Kwon, Y. S. and Chun, W. (2012) 3,4,5-Trihydroxycinnamic acid inhibits LPS-induced iNOS expression by suppressing NF-kappaB activation in BV2 microglial cells. Korean J. Physiol. Pharmacol. 16, 107-112.
  12. Lee, J. W., Kim, N. H., Kim, J. Y., Park, J. H., Shin, S. Y., Kwon, Y. S., Lee, H. J., Kim, S. S. and Chun, W. (2013) Aromadendrin inhibits lipopolysaccharide-induced nuclear translocation of NF-kappaB and phosphorylation of JNK in RAW 264.7 macrophage cells. Biomol. Ther. 21, 216-221.
  13. Lee, Y. J., Kim, S., Lee, S. J., Ham, I. and Whang, W. K. (2009) Antioxidant activities of new flavonoids from Cudrania tricuspidata root bark. Arch. Pharm. Res. 32, 195-200.
  14. Li, Q. and Verma, I. M. (2002) NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2, 725-734.
  15. Liu, X. H., Pan, L. L., Jia, Y. L., Wu, D., Xiong, Q. H., Wang, Y. and Zhu, Y. Z. (2013) A novel compound DSC suppresses lipopolysaccharide- induced inflammatory responses by inhibition of Akt/NFkappaB signalling in macrophages. Eur. J. Pharmacol. 708, 8-13.
  16. Madrid, L. V., Mayo, M. W., Reuther, J. Y. and Baldwin, A. S., Jr. (2001) Akt stimulates the transactivation potential of the RelA/p65 Subunit of NF-kappa B through utilization of the Ikappa B kinase and activation of the mitogen-activated protein kinase p38. J. Biol Chem. 276, 18934-18940.
  17. O'Connell, M. A., Bennett, B. L., Mercurio, F., Manning, A. M. and Mackman, N. (1998) Role of IKK1 and IKK2 in lipopolysaccharide signaling in human monocytic cells. J. Biol. Chem. 273, 30410-30414.
  18. Ock, J., Kim, S. and Suk, K. (2009) Anti-inflammatory effects of a fluorovinyloxyacetamide compound KT-15087 in microglia cells. Pharmacol. Res. 59, 414-422.
  19. Rehman, M. U., Yoshihisa, Y., Miyamoto, Y. and Shimizu, T. (2012) The anti-inflammatory effects of platinum nanoparticles on the lipopolysaccharide- induced inflammatory response in RAW 264.7 macrophages. Inflamm. Res. 61, 1177-1185.
  20. Rietschel, E. T. and Brade, H. (1992) Bacterial endotoxins. Sci. Am. 267, 54-61.
  21. Rushworth, S. A., Chen, X. L., Mackman, N., Ogborne, R. M. and O'Connell, M. A. (2005) Lipopolysaccharide-induced heme oxygenase- 1 expression in human monocytic cells is mediated via Nrf2 and protein kinase C. J. Immunol. 175, 4408-4415.
  22. Shao, D. Z. and Lin, M. (2008) Platonin inhibits LPS-induced NF-kappaB by preventing activation of Akt and IKKbeta in human PBMC. Inflamm. Res. 57, 601-606.
  23. Siebenlist, U., Franzoso, G. and Brown, K. (1994) Structure, regulation and function of NF-kappa B. Annu. Rev. Cell Biol. 10, 405-455.
  24. Sim, J. Y., Kim, M. A., Kim, M. J., Chun, W. and Kwon, Y. S. (2014) Acetylcholinesterase inhibitors from the stem of Zea Zea mays. Nat. Prod. Sci. 20, 13-16.
  25. Supinski, G. S., Ji, X. and Callahan, L. A. (2009) The JNK MAP kinase pathway contributes to the development of endotoxin-induced diaphragm caspase activation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297, R825-834.
  26. Sweet, M. J. and Hume, D. A. (1996) Endotoxin signal transduction in macrophages. J. Leukoc. Biol. 60, 8-26.
  27. Takeshima, E., Tomimori, K., Kawakami, H., Ishikawa, C., Sawada, S., Tomita, M., Senba, M., Kinjo, F., Mimuro, H., Sasakawa, C., Fujita, J. and Mori, N. (2009) NF-kappaB activation by Helicobacter pylori requires Akt-mediated phosphorylation of p65. BMC Microbiol. 9,36.
  28. Takii, T., Hayashi, M., Hiroma, H., Chiba, T., Kawashima, S., Zhang, H. L., Nagatsu, A., Sakakibara, J. and Onozaki, K. (1999) Serotonin derivative, N-(p-Coumaroyl)serotonin, isolated from safflower (Carthamus tinctorius L.) oil cake augments the proliferation of normal human and mouse fibroblasts in synergy with basic fibroblast growth factor (bFGF) or epidermal growth factor (EGF). J. Biochem. 125, 910-915.
  29. Takii, T., Kawashima, S., Chiba, T., Hayashi, H., Hayashi, M., Hiroma, H., Kimura, H., Inukai, Y., Shibata, Y., Nagatsu, A., Sakakibara, J., Oomoto, Y., Hirose, K. and Onozaki, K. (2003) Multiple mechanisms involved in the inhibition of proinflammatory cytokine production from human monocytes by N-(p-coumaroyl)serotonin and its derivatives. Int. Immunopharmacol. 3, 273-277.
  30. Vo, V. A., Lee, J. W., Chang, J. E., Kim, J. Y., Kim, N. H., Lee, H. J., Kim, S. S., Chun, W. and Kwon, Y. S. (2012) Avicularin inhibits lipopolysaccharide-induced inflammatory response by suppressing ERK phosphorylation in RAW 264.7 macrophages. Biomol. Ther. 20, 532-537.
  31. Vo, V. A., Lee, J. W., Kim, J. Y., Park, J. H., Lee, H. J., Kim, S. S., Kwon, Y. S. and Chun, W. (2014a) Phosphorylation of Akt mediates anti-inflammatory activity of 1-p-coumaronyl beta-D-glucoside against lipopolysaccharide-induced inflammation in RAW264.7 cells. Korean J. Physiol. Pharmacol. 18, 79-86.
  32. Vo, V. A., Lee, J. W., Shin, S. Y., Kwon, J. H., Lee, H. J., Kim, S. S., Kwon, Y. S. and Chun, W. (2014b) Methyl p-hydroxycinnamate suppresses lipopolysaccharide-induced inflammatory responses through Akt phosphorylation in RAW264.7 cells. Biomol. Ther. 22, 10-16.
  33. Wang, W. H., Gregori, G., Hullinger, R. L. and Andrisani, O. M. (2004) Sustained activation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase pathways by hepatitis B virus X protein mediates apoptosis via induction of Fas/FasL and tumor necrosis factor (TNF) receptor 1/TNF-alpha expression. Mol. Cell. Biol. 24, 10352-10365.
  34. Xu, C. Q., Liu, B. J., Wu, J. F., Xu, Y. C., Duan, X. H., Cao, Y. X. and Dong, J. C. (2010) Icariin attenuates LPS-induced acute inflammatory responses: involvement of PI3K/Akt and NF-kappaB signaling pathway. Eur. J. Pharmacol. 642, 146-153.
  35. Zhang, H. L., Nagatsu, A., Watanabe, T., Sakakibara, J. and Okuyama, H. (1997) Antioxidative compounds isolated from safflower (Carthamus tinctorius L.) oil cake. Chem. Pharm. Bull. (Tokyo) 45, 1910-1914.
  36. Zhang, W. Y., Lee, J. J., Kim, I. S., Kim, Y. and Myung, C. S. (2011) Stimulation of glucose uptake and improvement of insulin resistance by aromadendrin. Pharmacology 88, 266-274.
  37. Zhang, X., Hung, T. M., Phuong, P. T., Ngoc, T. M., Min, B. S., Song, K. S., Seong, Y. H. and Bae, K. (2006) Anti-inflammatory activity of flavonoids from Populus davidiana. Arch. Pharm. Res. 29, 1102-1108.
  38. Zong, Y., Sun, L., Liu, B., Deng, Y. S., Zhan, D., Chen, Y. L., He, Y., Liu, J., Zhang, Z. J., Sun, J. and Lu, D. (2012) Resveratrol inhibits LPSinduced MAPKs activation via activation of the phosphatidylinositol 3-kinase pathway in murine RAW 264.7 macrophage cells. PLoS One 7, e44107.

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