Abstract
Plant-extracted flavonoid glycosides have been reported to be bioactive compounds with pleiotropic functions, including antioxidant, anti-inflammatory, and anti-cancer effects. This study investigated the anti-inflammatory role of linarin (acacetin-7-rutinoside, which is found in Chrysanthemum indicum (Gam-Guk) and Dendranthema zawadskii (Gu-Jul-Cho)), on lipopolysaccharide-stimulated RAW264.7 macrophages. Linarin treatments exhibited no cytotoxicity up to a concentration of 30 μM, as assessed by MTT assay. The production of nitric oxide, an inflammatory mediator, was decreased by addition of linarin. The secretion of pro-inflammatory cytokines, interleukin-1β and interleukin-6, was significantly decreased in a dose-dependent manner. Linarin also decreased the phagocytic ability of macrophages following co-culture with fluorescent beads. In addition, expression levels of antigenpresenting surface markers, MHC II and CD80, were suppressed by linarin. Taken together, these results indicate that the flavonoid glycoside linarin has an anti-inflammatory effect, in part through the suppression of phagocytosis, cytokine production, and antigen presentation in macrophages.
Keywords: flavonoid, inflammation, cytokine, phagocytosis, antigen-presentation
References
- 1.Aderem A, Ulevitch RJ. Toll-like receptors in the induction of the innate immune response. Nature. 2000;406:782–787. doi: 10.1038/35021228. [DOI] [PubMed] [Google Scholar]
- 2.Chawla A, Nguyen KD, Goh YS. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 2011;11:738–749. doi: 10.1038/nri3071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Chawla A. Control of macrophage activation and function by PPARs. Circ. Res. 2010;106:1559–1569. doi: 10.1161/CIRCRESAHA.110.216523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gordon S. The role of the macrophage in immune regulation. Res. Immunol. 1998;149:685–688. doi: 10.1016/S0923-2494(99)80039-X. [DOI] [PubMed] [Google Scholar]
- 5.Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 2011;11:723–737. doi: 10.1038/nri3073. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kim Y, Han J, Sung J, Sung M, Choi Y, Jeong HS, Lee J. Anti-inflammatory activity of Chrysanthemum zawadskii var. latilobum leaf extract through haem oxygenase-1 induction. J. Funct. Foods. 2012;4:474–479. [Google Scholar]
- 7.Shim SY, Kang HS, Sun HJ, Lee YJ, Park JR, Chun SS, Song YH, Byun DS. Isolation and identification of flavonoids from Gujeolcho (Chrysanthemum zawadskii var. latilobum) as inhibitor of histamine release. Food Sci. Biotechnol. 2012;21:613–617. [Google Scholar]
- 8.Fernández S, Wasowski C, Paladini AC, Marder M. Sedative and sleepenhancing properties of linarin, a flavonoid-isolated from Valeriana officinalis. Pharmacol. Biochem. Be. 2004;77:399–404. doi: 10.1016/j.pbb.2003.12.003. [DOI] [PubMed] [Google Scholar]
- 9.Singh RP, Agrawal P, Yim D, Agarwal C, Agarwal R. Acacetin inhibits cell growth and cell cycle progression, and induces apoptosis in human prostate cancer cells: Structure-activity relationship with linarin and linarin acetate. Carcinogenesis. 2005;26:845–854. doi: 10.1093/carcin/bgi014. [DOI] [PubMed] [Google Scholar]
- 10.Lou H, Fan P, Perez RG, Lou H. Neuroprotective effects of linarin through activation of the PI3K/Akt pathway in amyloid-ß-induced neuronal cell death. Bioorgan. Med. Chem. 2011;19:4021–4027. doi: 10.1016/j.bmc.2011.05.021. [DOI] [PubMed] [Google Scholar]
- 11.Martínez-Vázquez M, Apan TR, Lastra AL, Bye RA. A comparative study of the analgesic and anti-inflammatory activities of pectolinarin isolated from Cirsium subcoriaceum and linarin isolated from Buddleia cordata. Planta Med. 1998;64:134–138. doi: 10.1055/s-2006-957390. [DOI] [PubMed] [Google Scholar]
- 12.Han S, Sung KH, Yim D, Lee S, Lee CK, Ha NJ, Kim K. The effect of linarin on lpslnduced cytokine production and nitric oxide inhibition in murine macrophages cell line RAW264.7. Arch. Pharm. Res. 2002;25:170–177. doi: 10.1007/BF02976559. [DOI] [PubMed] [Google Scholar]
- 13.Lee HA, Han JS. Anti-inflammatory effect of Perilla frutescens (L.) Britton var. frutescens extract in LPS-stimulated RAW 264.7 macrophages. Prev. Nutr. Food Sci. 2012;17:109–115. doi: 10.3746/pnf.2012.17.2.109. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Jin CH, Lee HJ, Park YD, Choi DS, Kim DS, Kang SY, Seo KI, Jeong IY. Isoegomaketone inhibits lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages through the heme oxygenase-1 induction and inhibition of the interferon-ß-STAT-1 pathway. J. Agr. Food Chem. 2009;58:860–867. doi: 10.1021/jf9033333. [DOI] [PubMed] [Google Scholar]
- 15.Araki N, Johnson MT, Swanson JA. A role for phosphoinositide 3-kinase in the completion of macropinocytosis and phagocytosis by macrophages. J. Cell Biol. 1996;135:1249–1260. doi: 10.1083/jcb.135.5.1249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Greenberg S, Grinstein S. Phagocytosis and innate immunity. Curr. Opin. Immunol. 2002;14:136–145. doi: 10.1016/S0952-7915(01)00309-0. [DOI] [PubMed] [Google Scholar]
- 17.Lee JK. Anti-inflammatory effects of eriodictyol in lipopolysaccharide stimulated raw 264.7 murine macrophages. Arch. Pharm. Res. 2011;34:671–679. doi: 10.1007/s12272-011-0418-3. [DOI] [PubMed] [Google Scholar]
- 18.Blanchette J, Jaramillo M, Olivier M. Signalling events involved in interferon-k-inducible macrophage nitric oxide generation. Immunology. 2003;108:513–522. doi: 10.1046/j.1365-2567.2003.01620.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Pan MH, Lai CS, Wang YJ, Ho CT. Acacetin suppressed LPS-induced upexpression of iNOS and COX-2 in murine macrophages and TPA-induced tumor promotion in mice. Biochem. Pharmacol. 2006;72:1293–1303. doi: 10.1016/j.bcp.2006.07.039. [DOI] [PubMed] [Google Scholar]
- 20.Coppack SW. Pro-inflammatory cytokines and adipose tissue. P. Nutr. Soc. 2001;60:349–356. doi: 10.1079/PNS2001110. [DOI] [PubMed] [Google Scholar]
- 21.Akira S, Hirano T, Taga T, Kishimoto T. Biology of multifunctional cytokines: IL 6 and related molecules (IL 1 and TNF) FASEB J. 1990;4:2860–2867. [PubMed] [Google Scholar]
- 22.van Kasteren SI, Overkleeft H, Ovaa H, Neefjes J. Chemical biology of antigen presentation by MHC molecules. Curr. Opin. Immunol. 2014;26:21–31. doi: 10.1016/j.coi.2013.10.005. [DOI] [PubMed] [Google Scholar]
- 23.Woldai S. The role of CD80 and CD86 in macrophage activation and its regulation following LPS stimulation. Ottawa, Canada: University of Ottawa; 2014. [Google Scholar]
- 24.Todd JA, Acha-Orbea H, Bell JI, Chao N, Fronek Z, Jacob CO, McDermott M, Sinha AA, Timmerman L, Steinman L. A molecular basis for MHC class IIassociated autoimmunity. Science. 1988;240:1003–1009. doi: 10.1126/science.3368786. [DOI] [PubMed] [Google Scholar]
- 25.Sansom DM, Manzotti CN, Zheng Y. What’s the difference between CD80 and CD86? Trends Immunol. 24: 313–318 (2003) [DOI] [PubMed]
- 26.Lim W, Gee K, Mishra S, Kumar A. Regulation of B7.1 costimulatory molecule is mediated by the IFN regulatory factor-7 through the activation of JNK in lipopolysaccharide-stimulated human monocytic cells. J. Immunol. 2005;175:5690–5700. doi: 10.4049/jimmunol.175.9.5690. [DOI] [PubMed] [Google Scholar]
- 27.Kim Y, Lee S, Yim D. Biological activities of linarin from Chrysanthemum zawadskii var. latilobum. Yakhak Hoeji. 2001;45:604–610. [Google Scholar]