Tangeretin Inhibits IL-12 Expression and NF-κB Activation in Dendritic Cells and Attenuates Colitis in Mice

Abstract

In the preliminary study, tangeretin (5,6,7,8,4′-pentamethoxy flavone), a major constituent of the pericarp of Citrus sp., inhibited TNF-α, IL-12, and IL-23 expression and nuclear factor kappa-B activation in lipopolysaccharide-stimulated dendritic cells; however, it did not affect IL-10 expression. Furthermore, tangeretin (5, 10, and 20 µM) suppressed the activation and translocation of nuclear factor kappa-B (p65) into the nuclei in vitro by inhibiting the binding of lipopolysaccharide on dendritic cells. Oral administration of tangeretin (10 and 20 mg/kg) suppressed the inflammatory responses, such as nuclear factor kappa-B and mitogen-activated protein kinase activation and myeloperoxidase activity, in the colon of mice with 2,4,6-trinitrobenzene sulfonic acid-induced colitis. Tangeretin increased 2,4,6-trinitrobenzene sulfonic acid-suppressed expression of tight junction proteins occludin, claudin-1, and ZO-1. Tangeretin also inhibited 2,4,6-trinitrobenzene sulfonic acid-induced differentiation of Th1 and Th17 cells as well as the expression of T-bet, RORγt, interferon-γ, IL-12, IL-17, and TNF-α. However, tangeretin increased 2,4,6-trinitrobenzene sulfonic acid-suppressed differentiation of regulatory T cells as well as the expression of Foxp3 and IL-10. These results suggest that oral administration of tangeretin may attenuate colitis by suppressing IL-12 and TNF-α expression and nuclear factor kappa-B activation through the inhibition of lipopolysaccharide binding on immune cells such as dendritic cells.

Key words

Citrus species - Rutaceae - tangeretin - dendritic cell - NF-κB - colitis

• References

• 1 Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 2011; 474: 298-306
• 2 Du Z, Hudcovic T, Mrazek J, Kozakova H, Srutkova D, Schwarzer M, Tlaskalova-Hogenova H, Kostovcik M, Kverka M. Development of gut inflammation in mice colonized with mucosa-associated bacteria from patients with ulcerative colitis. Gut Pathog 2015; 7: 32
• 3 Niess JH, Leithäuser F, Adler G, Reimann J. Commensal gut conditions. J Immunol 2008; 180: 559-568
• 4 Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity 2014; 41: 694-707
• 5 Owen JL, Mohamadzadeh M. Microbial activation of gut dendritic cells and the control of mucosal immunity. J Interferon Cytokine Res 2013; 33: 619-631
• 6 Rutella S, Locatelli F. Intestinal dendritic cells in the pathogenesis of inflammatory bowel disease. World J Gastroenterol 2011; 17: 3761-3775
• 7 Kaistha A, Levine J. Inflammatory bowel disease: the classic gastrointestinal autoimmune disease. Curr Probl Pediatr Adolesc Health Care 2014; 44: 328-334
• 8 Leppkes M, Becker C, Ivanov II, Hirth S, Wirtz S, Neufert C, Pouly S, Murphy AJ, Valenzuela DM, Yancopoulos GD, Becher B, Littman DR, Neurath MF. RORgamma-expressing TH17 cells induce murine chronic intestinal inflammation via redundant effects of IL-17A and IL-17F. Gastroenterology 2009; 136: 257-267
• 9 Assini JM, Mulvihill EE, Huff MW. Citrus flavonoids and lipid metabolism. Curr Opin Lipidol 2013; 24: 34-40
• 10 Meiyanto E, Hermawan A. Anindyajati. Natural products for cancer-targeted therapy: citrus flavonoids as potent chemopreventive agents. Asian Pac J Cancer Prev 2012; 13: 427-436
• 11 Wu X, Song M, Rakariyatham K, Zheng J, Guo S, Tang Z, Zhou S, Xiao H. Anti-inflammatory effects of 4′-demethylnobiletin, a major metabolite of nobiletin. J Funct Foods 2015; 19: 278-287
• 12 Yasuda N, Ishii T, Oyama D, Fukuta T, Agato Y, Sato A, Shimizu K, Asai T, Asakawa T, Kan T, Yamada S, Ohizumi Y, Oku N. Neuroprotective effect of nobiletin on cerebral ischemia-reperfusion injury in transient middle cerebral artery-occluded rats. Brain Res 2014; 1559: 46-54
• 13 Xiong Y, Chen D, Yu C, Lv B, Peng J, Wang J, Lin Y. Citrus nobiletin ameliorates experimental colitis by reducing inflammation and restoring impaired intestinal barrier function. Mol Nutr Food Res 2015; 59: 829-842
• 14 Lee YS, Cha BY, Choi SS, Choi BK, Yonezawa T, Teruya T, Nagai K, Woo JT. Nobiletin improves obesity and insulin resistance in high-fat diet-induced obese mice. J Nutr Biochem 2013; 24: 156-162
• 15 Jang SE, Ryu KR, Park SH, Chung S, Teruya Y, Han MJ, Woo JT, Kim DH. Nobiletin and tangeretin ameliorate scratching behavior in mice by inhibiting the action of histamine and the activation of NF-κB, AP-1 and p 38. Int Immunopharmacol 2013; 17: 502-507
• 16 Lopez A, Peyrin-Biroulet L. 5-Aminosalicylic acid and chemoprevention: does it work?. Dig Dis 2013; 31: 248-253
• 17 Robinson M. Medical therapy of inflammatory bowel disease for the 21st century. Eur J Surg 1998; 582: 90-98
• 18 Lee YY, Lee EJ, Park JS, Jang SE, Kim DH, Kim HS. Anti-inflammatory and antioxidant mechanism of tangeretin in activated microglia. J Neuroimmune Pharmacol 2016; 11: 294-305
• 19 Choi SY, Ko HC, Ko SY, Hwang JH, Park JG, Kang SH, Han SH, Yun SH, Kim SJ. Correlation between flavonoid content and the NO production inhibitory activity of peel extracts from various citrus fruits. Biol Pharm Bull 2007; 30: 772-778
• 20 Shu Z, Yang B, Zhao H, Xu B, Jiao W, Wang Q, Wang Z, Kuang H. Tangeretin exerts anti-neuroinflammatory effects via NF-κB modulation in lipopolysaccharide-stimulated microglial cells. Int Immunopharmacol 2014; 19: 275-282
• 21 Hagenlocher Y, Feilhauer K, Schäffer M, Bischoff SC, Lorentz A. Citrus peel polymethoxyflavones nobiletin and tangeretin suppress LPS- and IgE-mediated activation of human intestinal mast cells. Eur J Nutr DOI: 10.1007/s00394-016-1207-z. Advance online publication 28 March 2016
• 22 Xu JJ, Liu Z, Tang W, Wang GC, Chung HY, Liu QY, Zhuang L, Li MM, Li YL. Tangeretin from Citrus reticulata inhibits respiratory syncytial virus replication and associated inflammation in vivo . J Agric Food Chem 2015; 63: 9520-9527
• 23 Choi BK, Kim TW, Lee DR, Jung WH, Lim JH, Jung JY, Yang SH, Suh JW. A polymethoxy flavonoids-rich Citrus aurantium extract ameliorates ethanol-induced liver injury through modulation of AMPK and Nrf2-related signals in a binge drinking mouse model. Phytother Res 2015; 29: 1577-1584
• 24 Lutz MB, Kukutsch N, Ogilvie AL, Rossner S, Koch F, Romani N, Schuler G. An advanced culture method for generating large quantities of highly pure dendritic cells from mouse bone marrow. J Immunol Methods 1999; 223: 77-92
• 25 Lim SM, Kang GD, Jeong JJ, Choi HS, Kim DH. Neomangiferin modulates the Th17/Treg balance and ameliorates colitis in mice. Phytomedicine 2016; 23: 131-140
• 26 Jang SE, Han MJ, Kim SY, Kim DH. Lactobacillus plantarum CLP-0611 ameliorates colitis in mice by polarizing M1 to M2-like macrophages. Int Immunopharmacol 2014; 21: 186-192