Ebselen suppresses inflammation induced by Helicobacter pylori lipopolysaccharide via the p38 mitogen-activated protein kinase signaling pathway

Xu,Ling; Gong,Changguo; Li,Guangming; Wei,Jue; Wang,Ting; Meng,Wenying; Shi,Min; Wang,Yugang

doi:10.3892/mmr.2018.8641

Ebselen suppresses inflammation induced by Helicobacter pylori lipopolysaccharide via the p38 mitogen-activated protein kinase signaling pathway

Authors:
- Ling Xu
- Changguo Gong
- Guangming Li
- Jue Wei
- Ting Wang
- Wenying Meng
- Min Shi
- Yugang Wang
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Affiliations: Department of Gastroenterology, Shanghai Tongren Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200336, P.R. China, Department of Gastroenterology, Xinhua Hospital, Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
Published online on: February 27, 2018 https://doi.org/10.3892/mmr.2018.8641
Pages: 6847-6851

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Abstract

Ebselen is a seleno-organic compound that has been demonstrated to have antioxidant and anti-inflammatory properties. A previous study determined that ebselen inhibits airway inflammation induced by inhalational lipopolysaccharide (LPS), however, the underlying molecular mechanism remains to be elucidated. The present study investigated the effect of ebselen on the glutathione peroxidase (GPX)‑reactive oxygen species (ROS) pathway and interleukin‑8 (IL‑8) expression induced by Helicobacter pylori LPS in gastric cancer (GC) cells. Cells were treated with 200 ng/ml H. pylori‑LPS in the presence or absence of ebselen for various durations and concentrations (µmol/l). The expression of toll‑like receptor 4 (TLR4), GPX2, GPX4, p38 mitogen‑activated protein kinase (p38 MAPK), phosphorylated‑p38 MAPK, ROS production and IL‑8 expression were detected with western blotting or ELISA. The present study revealed that TLR4 expression was upregulated; however, GPX2 and GPX4 expression was reduced following treatment with H. pylori LPS, which led to increased ROS production, subsequently altering the IL‑8 expression level in GC cells. Additionally, it was determined that ebselen prevented the reduction in GPX2/4 levels induced by H. pylori LPS, however, TLR4 expression was not affected. Ebselen may also block the expression of IL‑8 by inhibiting phosphorylation of p38 MAPK. These data suggest ebselen may inhibit ROS production triggered by H. pylori LPS treatment via GPX2/4 instead of TLR4 signaling and reduce phosphorylation of p38 MAPK, resulting in altered production of IL‑8. Ebselen may, therefore, be a potential therapeutic agent to mediate H. pylori LPS-induced cell damage.

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1	Peek RM Jr and Blaser MJ: Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2:28–37. 2002. View Article : Google Scholar : PubMed/NCBI
2	Schistosomes, liver flukes and Helicobacter pylori. IARC working group on the evaluation of carcinogenic risks to humans; Lyon, 7–14 June 1994. IARC Monogr Eval Carcinog Risks Hum. 61:1–241. 1994.PubMed/NCBI
3	Hynes SO, Ferris JA, Szponar B, Wadström T, Fox JG, O'Rourke J, Larsson L, Yaquian E, Ljungh A, Clyne M, et al: Comparative chemical and biological characterization of the lipopolysaccharides of gastric and enterohepatic Helicobacter. Helicobacter. 9:313–323. 2004. View Article : Google Scholar : PubMed/NCBI
4	Esmaeilli D, Mobarez AM, Salmanian AH and Hosseini AZ: Bioactivity and immunological evaluation of LPS from different serotypes of Helicobacter pylori. Iran J Microbio. 5:142–146. 2013.
5	Ogawa T, Asai Y, Sakai Y, Oikawa M, Fukase K, Suda Y, Kusumoto S and Tamura T: Endotoxic and immunobiological activities of a chemically synthesized lipid A of Helicobacter pylori strain 206-1. FEMS Immunol Med Microbiol. 36:1–7. 2003. View Article : Google Scholar : PubMed/NCBI
6	Lepper PM, Triantafilou M, Schumann C, Schneider EM and Triantafilou K: Lipopolysaccharides from Helicobacter pylori can act as antagonists for Toll-like receptor 4. Cell Microbiol. 7:519–528. 2005. View Article : Google Scholar : PubMed/NCBI
7	Marthandan S, Hyland P, Pawelec G and Barnett Y: An investigation of the effects of the antioxidants, ebselen or N-acetyl cysteine on human peripheral blood mononuclear cells and T cells. Immun Ageing. 10:72013. View Article : Google Scholar : PubMed/NCBI
8	Haddad el-B, McCluskie K, Birrell MA, Dabrowski D, Pecoraro M, Underwood S, Chen B, De Sanctis GT, Webber SE, Foster ML and Belvisi MG: Differential effects of ebselen on neutrophil recruitment, chemokine and inflammatory mediator expression in a rat model of lipopolysaccharide-induced pulmonary inflammation. J Immunol. 169:974–982. 2002. View Article : Google Scholar : PubMed/NCBI
9	Bernardová K, Babica P, Marsálek B and Bláha L: Isolation and endotoxin activities of lipopolysaccharides from cyanobacterial cultures and complex water blooms and comparison with the effects of heterotrophic bacteria and green alga. J Appl Toxicol. 28:72–77. 2008. View Article : Google Scholar : PubMed/NCBI
10	Uno K, Kato K, Atsumi T, Suzuki T, Yoshitake J, Morita H, Ohara S, Kotake Y, Shimosegawa T and Yoshimura T: Toll-like receptor (TLR)2 induced through TLR4 signaling initiated by Helicobacter pylori cooperatively amplifies iNOS induction in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol. 293:G1004–G1012. 2007. View Article : Google Scholar : PubMed/NCBI
11	Chochi K, Ichikura T, Kinoshita M, Majima T, Shinomiya N, Tsujimoto H, Kawabata T, Sugasawa H, Ono S, Seki S and Mochizuki H: Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 patyway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin Cancer Res. 14:2909–2917. 2008. View Article : Google Scholar : PubMed/NCBI
12	Kawahara T, Teshima S, Oka A, Sugiyama T, Kishi K and Rokutan K: Type I Helicobacter pylori lipopolysaccharice stimulates toll-like receptor 4 and activates mitogen oxidase 1 in gastric pit cell. Infect Immun. 69:4382–4389. 2001. View Article : Google Scholar : PubMed/NCBI
13	Smith SM, Moran AP, Duggan SP, Ahmed SE, Mohamed AS, Windle HJ, O'Neill LA and Kelleher DP: Tribbles 3: A novel regulator of TLR2-mediated signaling in response to Helicobacter pylori lipopolysaccharide. J Immunol. 186:2462–2471. 2011. View Article : Google Scholar : PubMed/NCBI
14	Azad GK, Singh V, Mandal P, Singh P, Golla U, Baranwal S, Chauhan S and Tomar RS: Ebselen induces reactive oxygen species (ROS)-mediated cytotoxicity in Saccharomyces cerevisiae with inhibition of glutamate dehydrogenase being a target. FEBS Open Bio. 4:77–89. 2014. View Article : Google Scholar : PubMed/NCBI
15	Parnham MJ and Sies H: The early research and development of ebselen. Biochem Pharmacol. 86:1248–1253. 2013. View Article : Google Scholar : PubMed/NCBI
16	Yoshizumi M, Fujita Y, Izawa Y, Suzaki Y, Kyaw M, Ali N, Tsuchiya K, Kagami S, Yano S, Sone S and Tamaki T: Ebselen inhibits tumor necrosis factor-alpha-induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells. Exp Cell Res. 292:1–10. 2004. View Article : Google Scholar : PubMed/NCBI
17	Yoshizumi M, Kogame T, Suzaki Y, Fujita Y, Kyaw M, Kirima K, Ishizawa K, Tsuchiya K, Kagami S and Tamaki T: Ebselen attenuates oxidative stress-induced apoptosis via the inhibition of the c-Jun N-terminal kinase and activator protein-1 signalling pathway in PC12 cells. Br J Pharmacol. 136:1023–1032. 2002. View Article : Google Scholar : PubMed/NCBI
18	Sharma V, Tewari R, Sk UH, Joseph C and Sen E: Ebselen sensitizes glioblastoma cells to tumor necrosis Factor (TNFalpha)-induced apoptosis through two distinct pathways involving NF-kappaB downregulation and Fas-mediated formation of death inducing signaling complex. Int J Cancer. 123:2204–2212. 2008. View Article : Google Scholar : PubMed/NCBI
19	Yang CF, Shen HM and Ong CN: Ebselen induces apoptosis in HepG-2 cells through rapid depletion of intracellular thiols. Arch Biochem Biophys. 374:142–152. 2000. View Article : Google Scholar : PubMed/NCBI
20	Luo Z, Liang L, Sheng J, Pang Y, Li J, Huang L and Li X: Synthesis and biological evaluation of a new series of ebselen derivatives as glutathione peroxidase (GPX) mimics and cholinesterase inhibitors against Alzheimer's disease. Bioorg Med Chem. 22:1355–1361. 2014. View Article : Google Scholar : PubMed/NCBI
21	Wang X, Yun JW and Lei XG: Glutathione peroxidase mimic ebselen improves glucose-stimulated insulin secretion in murine islets. Antioxid Redox Signal. 20:191–203. 2014. View Article : Google Scholar : PubMed/NCBI