Kaempferol inhibits multiple pathways involved in the secretion of inflammatory mediators from LPS‑induced rat intestinal microvascular endothelial cells

Bian,Yifei; Liu,Ping; Zhong,Jia; Hu,Yusheng; Fan,Yingsai; Zhuang,Shen; Liu,Zhongjie

doi:10.3892/mmr.2018.9777

Kaempferol inhibits multiple pathways involved in the secretion of inflammatory mediators from LPS‑induced rat intestinal microvascular endothelial cells

Authors:
- Yifei Bian
- Ping Liu
- Jia Zhong
- Yusheng Hu
- Yingsai Fan
- Shen Zhuang
- Zhongjie Liu
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Affiliations: Division of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, China Agricultural University, Beijing 100193, P.R. China
Published online on: December 18, 2018 https://doi.org/10.3892/mmr.2018.9777
Pages: 1958-1964

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Abstract

Inflammatory bowel disease (IBD) is a chronic, idiopathic inflammatory disease of the small and/or large intestine. Endothelial expression of inflammatory mediators, including cytokines and adhesion molecules, serves a critical role in the initiation and progression of IBD. The dietary flavonoid, kaempferol, has been reported to inhibit expression of inflammatory mediators; however, the underlying mechanisms require further investigation. In the present study, a novel molecular mechanism of kaempferol against IBD was identified. The potential anti‑inflammatory effect of kaempferol in a cellular model of intestinal inflammation was assessed using lipopolysaccharide (LPS)‑induced rat intestinal microvascular endothelial cells (RIMVECs), and an underlying key molecular mechanism was identified. RIMVECs were pretreated with kaempferol of various concentrations (12.5, 25 and 50 µM) followed by LPS (10 µg/ml) stimulation. ELISA was used to examine the protein levels of tumor necrosis factor‑α (TNF‑α), interleukin‑1β (IL‑1β), IL‑6, intercellular adhesion molecule-1 (ICAM‑1) and vascular cell adhesion molecule-1 (VCAM‑1) in the supernatant. Protein expression levels of Toll‑like receptor 4 (TLR4), nuclear factor‑κB (NF‑κB) p65, inhibitor of NF‑κB, mitogen‑activated protein kinase p38 and signal transducer and activator of transcription (STAT) in cells were measured by western blotting. Kaempferol significantly reduced the overproduction of TNF‑α, IL‑1β, interleukin‑6, ICAM‑1 and VCAM‑1 induced by LPS, indicating the negative regulation of kaempferol in TLR4, NF‑κB and STAT signaling underlying intestinal inflammation. The present results provide support for the potential use of kaempferol as an effective therapeutic agent for IBD treatment.

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1	Vezza T, Rodríguez-Nogales A, Algieri F, Utrilla MP, Rodriguez-Cabezas ME and Galvez J: Flavonoids in inflammatory bowel disease: A review. Nutrients. 8:2112016. View Article : Google Scholar : PubMed/NCBI
2	Moldoveanu AC, Diculescu M and Braticevici CF: Cytokines in inflammatory bowel disease. Rom J Intern Med. 53:118–127. 2015.PubMed/NCBI
3	Klampfer L: Cytokines, inflammation and colon cancer. Curr Cancer Drug Targets. 11:451–466. 2011. View Article : Google Scholar : PubMed/NCBI
4	Liu TC and Stappenbeck TS: Genetics and pathogenesis of inflammatory bowel disease. Annu Rev Pathol. 11:127–148. 2016. View Article : Google Scholar : PubMed/NCBI
5	de Boer NK, van Bodegraven AA, Jharap B, de Graaf P and Mulder CJ: Drug Insight: Pharmacology and toxicity of thiopurine therapy in patients with IBD. Nat Clin Pract Gastroenterol Hepatol. 4:686–694. 2007. View Article : Google Scholar : PubMed/NCBI
6	Dodda D, Chhajed R and Mishra J: Protective effect of quercetin against acetic acid induced inflammatory bowel disease (IBD) like symptoms in rats: Possible morphological and biochemical alterations. Pharmacol Rep. 66:169–173. 2014. View Article : Google Scholar : PubMed/NCBI
7	Park MY, Ji GE and Sung MK: Dietary kaempferol suppresses inflammation of dextran sulfate sodium-induced colitis in mice. Dig Dis Sci. 57:355–363. 2012. View Article : Google Scholar : PubMed/NCBI
8	Yao L, Yao J, Han C, Yang J, Chaudhry MT, Wang S, Liu H and Yin Y: Quercetin, Inflammation and Immunity. Nutrients. 8:1672016. View Article : Google Scholar : PubMed/NCBI
9	Bhaskar S, Sudhakaran PR and Helen A: Quercetin attenuates atherosclerotic inflammation and adhesion molecule expression by modulating TLR-NF-κB signaling pathway. Cell Immunol. 310:131–140. 2016. View Article : Google Scholar : PubMed/NCBI
10	Cho SY, Park SJ, Kwon MJ, Jeong TS, Bok SH, Choi WY, Jeong WI, Ryu SY, Do SH, Lee CS, et al: Quercetin suppresses proinflammatory cytokines production through MAP kinases andNF-kappaB pathway in lipopolysaccharide-stimulated macrophage. Mol Cell Biochem. 243:153–160. 2003. View Article : Google Scholar : PubMed/NCBI
11	Park MY, Kwon HJ and Sung MK: Evaluation of aloin and aloe-emodin as anti-inflammatory agents in aloe by using murine macrophages. Biosci Biotechnol Biochem. 73:828–832. 2009. View Article : Google Scholar : PubMed/NCBI
12	Binion DG, West GA, Ina K, Ziats NP, Emancipator SN and Fiocchi C: Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease. Gastroenterology. 112:1895–1907. 1997. View Article : Google Scholar : PubMed/NCBI
13	Swerlick RA and Lawley TJ: Role of microvascular endothelial cells in inflammation. J Invest Dermatol. 100 Suppl:111S–115S. 1993. View Article : Google Scholar : PubMed/NCBI
14	Duan H, Zhang Y, Xu J, Qiao J, Suo Z, Hu G and Mu X: Effect of anemonin on NO, ET-1 and ICAM-1 production in rat intestinal microvascular endothelial cells. J Ethnopharmacol. 104:362–366. 2006. View Article : Google Scholar : PubMed/NCBI
15	Suo Z, Mu X, Xu J, Wang Z, Wang X, Duan H, Hu G, Yang Z and Huang H: In vitro culture of rat intestinal mucous microvascular endothelial cells. Acta Anatomica Sinica. 36:214–217. 2005.(In Chinese).
16	Kasper JY, Hermanns MI, Cavelius C, Kraegeloh A, Jung T, Danzebrink R, Unger RE and Kirkpatrick CJ: The role of the intestinal microvasculature in inflammatory bowel disease: Studies with a modified Caco-2 model including endothelial cells resembling the intestinal barrier in vitro. Int J Nanomedicine. 11:6353–6364. 2016. View Article : Google Scholar : PubMed/NCBI
17	Francescone R, Hou V and Grivennikov SI: Cytokines, IBD, and colitis-associated cancer. Inflam Bowel Dis. 21:409–418. 2015. View Article : Google Scholar
18	Lu JT, Xu AT, Shen J and Ran ZH: Crosstalk between intestinal epithelial cell and adaptive immune cell in intestinal mucosal immunity. J Gastroenterol Hepatol. 32:975–980. 2017. View Article : Google Scholar : PubMed/NCBI
19	Hu YS, Lin RY, Bian YF, Fan K and Liu ZJ: Protective effect of kushenlu on lipopolysaccharide-induced small intestinal inflammation in rats. Int J Pharmacol. 13:473–480. 2017. View Article : Google Scholar
20	Liu J, Xue J, Zhu Z, Hu G and Ren X: Lactic acid inhibits NF-κB activation by lipopolysaccharide in rat intestinal mucosa microvascular endothelial cells. Agr Sci China. 10:954–959. 2011. View Article : Google Scholar
21	Xavier RJ and Podolsky DK: Unravelling the pathogenesis of inflammatory bowel disease. Nature. 448:427–434. 2007. View Article : Google Scholar : PubMed/NCBI
22	Xanthoulea S, Pasparakis M, Kousteni S, Brakebusch C, Wallach D, Bauer J, Lassmann H and Kollias G: Tumor Necrosis Factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. J Exp Med. 200:367–376. 2004. View Article : Google Scholar : PubMed/NCBI
23	Binion DG and Rafiee P: Is inflammatory bowel disease a vascular disease? Targeting angiogenesis improves chronic inflammation in inflammatory bowel disease. Gastroenterology. 136:400–403. 2009. View Article : Google Scholar : PubMed/NCBI
24	Medda R, Lyros O, Schmidt JL, Jovanovic N, Nie L, Link BJ, Otterson MF, Stoner GD, Shaker R and Rafiee P: Anti inflammatory and anti angiogenic effect of black raspberry extract on human esophageal and intestinal microvascular endothelial cells. Microvasc Res. 97:167–180. 2015. View Article : Google Scholar : PubMed/NCBI
25	Dhawan A, Friedrichs J, Bonin MV, Bejestani EP, Werner C, Wobus M, Chavakis T and Bornhäuser M: Breast cancer cells compete with hematopoietic stem and progenitor cells for intercellular adhesion molecule 1-mediated binding to the bone marrow microenvironment. Carcinogenesis. 37:759–767. 2016. View Article : Google Scholar : PubMed/NCBI
26	Chen X, Yang X, Liu T, Guan M, Feng X, Dong W, Chu X, Liu J, Tian X, Ci X, et al: Kaempferol regulates MAPKs and NF-κB signaling pathways to attenuate LPS-induced acute lung injury in mice. Int Immunopharmacol. 14:209–216. 2012. View Article : Google Scholar : PubMed/NCBI
27	Comalada M, Camuesco D, Sierra S, Ballester I, Xaus J, Gálvez J and Zarzuelo A: In vivo quercitrin anti-inflammatory effect involves release of quercetin, which inhibits inflammation through down-regulation of the NF-kappaB pathway. Eur J Immunol. 35:584–592. 2005. View Article : Google Scholar : PubMed/NCBI
28	Cui L, Feng L, Zhang ZH and Jia XB: The anti-inflammation effect of baicalin on experimental colitis through inhibiting TLR4/NF-κB pathway activation. Int Immunopharmacol. 23:294–303. 2014. View Article : Google Scholar : PubMed/NCBI
29	Li Z, Zhang DK, Yi WQ, Ouyang Q, Chen YQ and Gan HT: NF-kappaB p65 antisense oligonucleotides may serve as a novel molecular approach for the treatment of patients with ulcerative colitis. Arch Med Res. 39:729–734. 2008. View Article : Google Scholar : PubMed/NCBI
30	Lucas K and Maes M: Role of the toll like receptor (TLR) radical cycle in chronic inflammation: Possible treatments targeting the TLR4 pathway. Mol Neurobiol. 48:190–204. 2013. View Article : Google Scholar : PubMed/NCBI
31	Akira S, Hoshino K and Kaisho T: The role of Toll-like receptors and MyD88 in innate immune responses. J Endotoxin Res. 6:383–387. 2000. View Article : Google Scholar : PubMed/NCBI
32	Chen C, Chen YH and Lin WW: Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. Immunology. 97:124–129. 1999. View Article : Google Scholar : PubMed/NCBI
33	Liu W, Liu Y, Wang Z, Yu T, Lu Q and Chen H: Suppression of MAPK and NF-κB pathways by schisandrin B contributes to attenuation of DSS-induced mice model of inflammatory bowel disease. Pharmazie. 70:598–603. 2015.PubMed/NCBI
34	Amiot A and Peyrin-Biroulet L: Current, new and future biological agents on the horizon for the treatment of inflammatory bowel diseases. Ther Adv Gastroenter. 8:66–82. 2015. View Article : Google Scholar
35	Huang CH, Jan RL, Kuo CH, Chu YT, Wang WL, Lee MS, Chen HN and Hung CH: Natural flavone kaempferol suppresses chemokines expression in human monocyte THP-1 cells through MAPK pathways. J Food Sci. 75:H254–H259. 2010. View Article : Google Scholar : PubMed/NCBI
36	Yoon HY, Lee EG, Lee H, Cho IJ, Choi YJ, Sung MS, Yoo HG and Yoo WH: Kaempferol inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs. Int J Mol Med. 32:971–977. 2013. View Article : Google Scholar : PubMed/NCBI
37	Lian JJ, Cheng BF, Gao YX, Xue H, Wang L, Wang M, Yang HJ and Feng ZW: Protective effect of kaempferol, a flavonoid widely present in varieties of edible plants, on IL-1β-induced inflammatory response via inhibiting MAPK, Akt, and NF-κB signalling in SW982 cells. J Funct Foods. 27:214–222. 2016. View Article : Google Scholar
38	Slattery ML, Lundgreen A, Kadlubar SA, Bondurant KL and Wolff RK: JAK/STAT/SOCS-signaling pathway and colon and rectal cancer. Mol Carcinog. 52:155–166. 2013. View Article : Google Scholar : PubMed/NCBI
39	Nunes C, Almeida L, Barbosa RM and Laranjinha J: Luteolin suppresses the JAK/STAT pathway in a cellular model of intestinal inflammation. Food Funct. 8:387–396. 2017. View Article : Google Scholar : PubMed/NCBI
40	Zhao HM, Xu R, Huang XY, Cheng SM, Huang MF, Yue HY, Wang X, Zou Y, Lu AP and Liu DY: Curcumin suppressed activation of dendritic cells via JAK/STAT/SOCS signal in mice with experimental colitis. Front Pharmacol. 7:4552016. View Article : Google Scholar : PubMed/NCBI
41	Gong JH and Kang YH: Kaempferol inhibits chemokine expression and attenuates airway inflammation by suppressing STAT/JAK and NF-kB activity in human airway epithelial cells. FASEB J. 25 Suppl 1:lb1–1130.6. 2011.