Browse > Article
http://dx.doi.org/10.4062/biomolther.2016.027

Pyrrole-Derivative of Chalcone, (E)-3-Phenyl-1-(2-Pyrrolyl)-2-Propenone, Inhibits Inflammatory Responses via Inhibition of Src, Syk, and TAK1 Kinase Activities  

Yang, Sungjae (Department of Genetic Engineering, Sungkyunkwan University)
Kim, Yong (Department of Genetic Engineering, Sungkyunkwan University)
Jeong, Deok (Department of Genetic Engineering, Sungkyunkwan University)
Kim, Jun Ho (Department of Genetic Engineering, Sungkyunkwan University)
Kim, Sunggyu (Research and Business Foundation, Sungkyunkwan University)
Son, Young-Jin (College of Pharmacy, Sunchon National University)
Yoo, Byong Chul (Colorectal Cancer Branch, Research Institute, National Cancer Center)
Jeong, Eun Jeong (Department of Science Education, Kangwon National University)
Kim, Tae Woong (Department of Biochemistry, Kangwon National University)
Han Lee, In-Sook (Department of Science Education, Kangwon National University)
Cho, Jae Youl (Department of Genetic Engineering, Sungkyunkwan University)
Publication Information
Biomolecules & Therapeutics / v.24, no.6, 2016 , pp. 595-603 More about this Journal
Abstract
(E)-3-Phenyl-1-(2-pyrrolyl)-2-propenone (PPP) is a pyrrole derivative of chalcone, in which the B-ring of chalcone linked to ${\beta}$-carbon is replaced by pyrrole group. While pyrrole has been studied for possible Src inhibition activity, chalcone, especially the substituents on the B-ring, has shown pharmaceutical, anti-inflammatory, and anti-oxidant properties via inhibition of NF-${\kappa}B$ activity. Our study is aimed to investigate whether this novel synthetic compound retains or enhances the pharmaceutically beneficial activities from the both structures. For this purpose, inflammatory responses of lipopolysaccharide (LPS)-treated RAW264.7 cells were analyzed. Nitric oxide (NO) production, inducible NO synthase (iNOS) and tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) mRNA expression, and the intracellular inflammatory signaling cascade were measured. Interestingly, PPP strongly inhibited NO release in a dose-dependent manner. To further investigate this anti-inflammatory activity, we identified molecular pathways by immunoblot analyses of nuclear fractions and whole cell lysates prepared from LPS-stimulated RAW264.7 cells with or without PPP pretreatment. The nuclear levels of p50, c-Jun, and c-Fos were significantly inhibited when cells were exposed to PPP. Moreover, according to the luciferase reporter gene assay after cotransfection with either TRIF or MyD88 in HEK293 cells, NF-${\kappa}B$-mediated luciferase activity dose-dependently diminished. Additionally, it was confirmed that PPP dampens the upstream signaling cascade of NF-${\kappa}B$ and AP-1 activation. Thus, PPP inhibited Syk, Src, and TAK1 activities induced by LPS or induced by overexpression of these genes. Therefore, our results suggest that PPP displays anti-inflammatory activity via inhibition of Syk, Src, and TAK1 activity, which may be developed as a novel anti-inflammatory drug.
Keywords
Pyrrole; Chalcone; Anti-inflammatory activity; Macrophages; NF-${\kappa}B$;
Citations & Related Records
Times Cited By KSCI : 13  (Citation Analysis)
연도 인용수 순위
1 Brown, K., Park, S., Kanno, T., Franzoso, G. and Siebenlist, U. (1993) Mutual regulation of the transcriptional activator $NF-{\kappa}B$ and its inhibitor, $I{\kappa}B{\alpha}$. Proc. Natl. Acad. Sci. U.S.A. 90, 2532-2536.   DOI
2 Byeon, S. E., Yi, Y.-S., Oh, J., Yoo, B. C., Hong, S. and Cho, J. Y. (2012) The role of Src kinase in macrophage-mediated inflammatory responses. Mediators Inflamm. 2012, 512926.
3 Byeon, S. E., Lee, Y. G., Kim, B. H., Shen, T., Lee, S. Y., Park, H. J., Park, S.-C., Rhee, M. H. and Cho, J. Y. (2008) Surfactin blocks NO production in lipopolysaccharide-activated macrophages by inhibiting $NF-{\kappa}B$ activation. J. Microbiol. Biotechnol. 18, 1984-1989.
4 Ajibade, A. A., Wang, H. Y. and Wang, R. F. (2013) Cell type-specific function of TAK1 in innate immune signaling. Trends Immunol. 34, 307-316.   DOI
5 Baek, K. S., Hong, Y. D., Kim, Y., Sung, N. Y., Yang, S., Lee, K. M., Park, J. Y., Park, J. S., Rho, H. S., Shin, S. S. and Cho, J. Y. (2015) Anti-inflammatory activity of AP-SF, a ginsenoside-enriched fraction, from Korean ginseng. J. Ginseng Res. 39, 155-161.   DOI
6 Byeon, S. E., Yu, T., Yang, Y., Lee, Y. G., Kim, J. H., Oh, J., Jeong, H. Y., Hong, S., Yoo, B. C., Cho, W. J., Hong, S. and Cho, J. Y. (2013) Hydroquinone regulates hemeoxygenase-1 expression via modulation of Src kinase activity through thiolation of cysteine residues. Free Radic. Biol. Med. 57, 105-118.   DOI
7 Cho, B. O., Ryu, H. W., So, Y., Lee, C. W., Jin, C. H., Yook, H. S., Jeong, Y. W., Park, J. C. and Jeong, I. Y. (2014) Anti-Inflammatory Effect of Mangostenone F in Lipopolysaccharide-Stimulated RAW264.7 Macrophages by Suppressing $NF-{\kappa}B$ and MAPK Activation. Biomol. Ther. (Seoul) 22, 288-294.   DOI
8 Chow, J. C., Young, D. W., Golenbock, D. T., Christ, W. J. and Gusovsky, F. (1999) Toll-like receptor-4 mediates lipopolysaccharide-induced signal transduction. J. Biol. Chem. 274, 10689-10692.   DOI
9 Dincer, S., Cetin, K. T., Onay-Besikci, A. and Olgen, S. (2013) Synthesis, biological evaluation and docking studies of new pyrrolo [2, 3-d] pyrimidine derivatives as Src family-selective tyrosine kinase inhibitors. J. Enzyme Inhib. Med. Chem. 28, 1080-1087.   DOI
10 Kim, Y., Jeong, E. J., Han Lee, I. S., Kim, M. Y. and Cho, J. Y. (2016) (E)-3-(3-methoxyphenyl)-1-(2-pyrrolyl)-2-propenone displays suppression of inflammatory responses via inhibition of Src, Syk, and $NF-{\kappa}B$. Korean J. Physiol. Pharmacol. 20, 91-99.   DOI
11 Kishimoto, K., Matsumoto, K. and Ninomiya-Tsuji, J. (2000) TAK1 mitogen-activated protein kinase kinase kinase is activated by autophosphorylation within its activation loop. J. Biol. Chem. 275, 7359-7364.   DOI
12 Lumeng, C. N. and Saltiel, A. R. (2011) Inflammatory links between obesity and metabolic disease. J. Clin. Invest. 121, 2111-2117.   DOI
13 Kim, M. Y., Yoo, B. C. and Cho, J. Y. (2014b) Ginsenoside-Rp1-induced apolipoprotein A-1 expression in the LoVo human colon cancer cell line. J. Ginseng Res. 38, 251-255.   DOI
14 Elinav, E., Nowarski, R., Thaiss, C. A., Hu, B., Jin, C. and Flavell, R. A. (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat. Rev. Cancer 13, 759-771.   DOI
15 Jeon, B. R., Kim, S. J., Hong, S. B., Park, H. J., Cho, J. Y. and Rhee, M. H. (2015) The inhibitory mechanism of crude saponin fraction from Korean Red Ginseng in collagen-induced platelet aggregation. J. Ginseng Res. 39, 279-285.   DOI
16 Kim, K. H., Kim, T. S., Lee, J. G., Park, J. K., Yang, M., Kim, J. M., Jo, E. K. and Yuk, J. M. (2014a) Characterization of Proinflammatory Responses and Innate Signaling Activation in Macrophages Infected with Mycobacterium scrofulaceum. Immune Netw. 14, 307-320.   DOI
17 Lee, N., Jung, Y. S., Lee, H. Y., Kang, N., Park, Y. J., Hwang, J. S., Bahk, Y. Y., Koo, J. and Bae, Y. S. (2014b) Mouse neutrophils express functional umami taste receptor T1R1/T1R3. BMB Rep. 47, 649-654.   DOI
18 Lee, H. S., Lee, G. S., Kim, S. H., Kim, H. K., Suk, D. H. and Lee, D. S. (2014a) Anti-oxidizing effect of the dichloromethane and hexane fractions from Orostachys japonicus in LPS-stimulated RAW 264.7 cells via upregulation of Nrf2 expression and activation of MAPK signaling pathway. BMB Rep. 47, 98-103.   DOI
19 Lee, I. S. H., Jeoung, E. J. and Lee, C. K. (2013) Synthesis and NMR Studies of (E)-1-Aryl-3-(2-pyrrolyl)-2-propenones and (E)-3-Aryl-1-(2-pyrrolyl)-2-propenones. Bull. Korean Chem. Soc. 34, 936-942.   DOI
20 Lee, J.-H., Jung, H. S., Giang, P. M., Jin, X., Lee, S., Son, P. T., Lee, D., Hong, Y.-S., Lee, K. and Lee, J. J. (2006) Blockade of nuclear $factor-{\kappa}B$ signaling pathway and anti-inflammatory activity of cardamomin, a chalcone analog from Alpinia conchigera. J. Pharmacol. Exp. Ther. 316, 271-278.
21 Lee, Y. J., Han, J. Y., Lee, C. G., Heo, K., Park, S. I., Park, Y. S., Kim, J. S., Yang, K. M., Lee, K. J., Kim, T. H., Rhee, M. H. and Kim, S. D. (2014c) Korean Red Ginseng saponin fraction modulates radiation effects on lipopolysaccharide-stimulated nitric oxide production in RAW264.7 macrophage cells. J. Ginseng Res. 38, 208-214.   DOI
22 Rittirsch, D., Flierl, M. A. and Ward, P. A. (2008) Harmful molecular mechanisms in sepsis. Nat. Rev. Immunol. 8, 776-787.   DOI
23 Nahid, M. A., Satoh, M. and Chan, E. K. (2011) MicroRNA in TLR signaling and endotoxin tolerance. Cell. Mol. Immunol. 8, 388-403.   DOI
24 O'Neill, L. A. (2002) Signal transduction pathways activated by the IL-1 receptor/toll-like receptor superfamily. Curr. Top. Microbiol. Immunol. 270, 47-61.
25 Pauwels, R., Balzarini, J., Baba, M., Snoeck, R., Schols, D., Herdewijn, P., Desmyter, J. and De Clercq, E. (1988) Rapid and automated tetrazolium-based colorimetric assay for the detection of anti-HIV compounds. J. Virol. Methods 20, 309-321.   DOI
26 Screaton, G., Mongkolsapaya, J., Yacoub, S. and Roberts, C. (2015) New insights into the immunopathology and control of dengue virus infection. Nat. Rev. Immunol. 15, 745-759.   DOI
27 Shao, H. J., Lou, Z., Jeong, J. B., Kim, K. J., Lee, J. and Lee, S. H. (2015) Tolfenamic Acid Suppresses Inflammatory Stimuli-Mediated Activation of $NF-{\kappa}B$ Signaling. Biomol. Ther. (Seoul) 23, 39-44.   DOI
28 Tran, V. G., Cho, H. R. and Kwon, B. (2014) IL-33 Priming Enhances Peritoneal Macrophage Activity in Response to Candida albicans. Immune Netw. 14, 201-206.   DOI
29 Yang, K.-J., Shin, S., Piao, L., Shin, E., Li, Y., Park, K. A., Byun, H. S., Won, M., Hong, J., Kweon, G. R., Hur, G. M., Seok, J. H., Chun, T., Brazil, D. P., Hemmings, B. A. and Park, J. (2008) Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding. J. Biol. Chem. 283, 1480-1491.   DOI
30 Yang, W. S., Lee, J., Kim, T. W., Kim, J. H., Lee, S., Rhee, M. H., Hong, S. and Cho, J. Y. (2012) $Src/NF-{\kappa}B$-targeted inhibition of LPS-induced macrophage activation and dextran sodium sulphate-induced colitis by Archidendron clypearia methanol extract. J. Ethnopharmacol. 142, 287-293.   DOI
31 Yang, Y., Yang, W. S., Yu, T., Yi, Y.-S., Park, J. G., Jeong, D., Kim, J. H., Oh, J. S., Yoon, K., Kim, J.-H. and Cho, J. Y. (2014) Novel anti-inflammatory function of NSC95397 by the suppression of multiple kinases. Biochem. Pharmacol. 88, 201-215.
32 Akira, S. and Takeda, K. (2004) Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499-511.   DOI
33 Yu, T., Li, Y. J., Bian, A. H., Zuo, H. B., Zhu, T. W., Ji, S. X., Kong, F., Yin de, Q., Wang, C. B., Wang, Z. F., Wang, H. Q., Yang, Y., Yoo, B. C. and Cho, J. Y. (2014) The regulatory role of activating transcription factor 2 in inflammation. Mediators Inflamm. 2014, 950472.