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Digestive Diseases and Sciences

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01-10-2013 | Original Article

Abnormal Expression of Toll-Like Receptor 4 Is Associated with Susceptibility to Ethanol-Induced Gastric Mucosal Injury in Mice

Authors: Hui-hui Ye, Rong Hua, Le Yu, Ke-jian Wu, Su-juan Fei, Xia Qin, Ying Song, Jun-li Cao, Yong-mei Zhang

Published in: Digestive Diseases and Sciences | Issue 10/2013

Abstract

Background and Aims

Toll-like receptor 4 (TLR4) contributes to ethanol-induced gastric mucosal injury. This study aimed to determine its precise role in this pathogenic state and the related signaling pathway.

Methods

Ethanol-induced gastric mucosal injury models were generated in TLR4^−/− mice (C3H/HeJ: point mutation; C57BL/10ScNJ: gene deletion), their respective TLR4^+/+ wild-type counterparts, and heterozygous TLR4^+/− mice. Lipopolysaccharide (LPS) or pyrrolidine dithiocarbamate (PDTC) was injected intraperitoneally 1 h or 30 min before ethanol administration. At 1 h post-ethanol treatment, gastric or serum specimens were evaluated.

Results

Ethanol intra-gastric administration induced significant gastric mucosal injury in all mice, but the damaged area was larger in TLR4^−/− mice. LPS preconditioning and up-regulated TLR4 expression led to significantly larger areas of gastric mucosal damage. Upon ethanol administration, TLR4^+/+, and not TLR4^−/−, mice showed significant increases in TLR4, myeloid differentiation factor 88 (MyD88), cytoplasmic high mobility group box 1 (HMGB1), and nuclear factor-kappa B p65 (NF-κB p65). PDTC pretreatment significantly attenuated the ethanol-induced gastric mucosal damaged areas, inhibited nuclear NF-κB p65 expression, and suppressed HMGB1 translocation out of the nucleus. In addition, PDTC pretreatment reduced ethanol-stimulated expression of the inflammatory modulators, interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α), in serum.

Conclusions

Both deficient and excessive expression of TLR4 promotes ethanol-induced gastric mucosal injury. The underlying mechanism involves the MyD88/NF-κB signaling pathway and the HMGB1, TLR4 activator ligand. The increased expression of HMGB1 may lead to increased secretion and binding to TLR4, further stimulating the TLR4/MyD88/NF-κB signaling pathway and aggravating the ethanol-induced gastric mucosal injury.

Li NS, Luo XJ, Zhang YS, He L, Liu YZ, Peng J. Phloroglucinol protects gastric mucosa against ethanol-induced injury through regulating myeloperoxidase and catalase activities. Fundam Clin Pharmacol. 2011;25:462–468.PubMedCrossRef

Li YG, Ji DF, Lin TB, Zhong S, Hu GY, Chen S. Protective effect of sericin peptide against alcohol-induced gastric injury in mice. Chin Med J (Engl). 2008;121:2083–2087.

Hong J, Yi SX, Huang Y, et al. Effect of plasma of healthy subjects undergoing moxibustion on ethanol-injured human gastric epithelial GES-1 cells in vitro and the involved mitochondrial apoptosis pathway. Zhen Ci Yan Jiu. 2011;36:157–163, 192.

Alqasoumi S, Al-Sohaibani M, Al-Howiriny T, Al-Yahya M, Rafatullah S. Rocket “Eruca sativa”: a salad herb with potential gastric anti-ulcer activity. World J Gastroenterol. 2009;15:1958–1965.PubMedCrossRef

Rios ER, Rocha NF, Venancio ET, et al. Mechanisms involved in the gastroprotective activity of esculin on acute gastric lesions in mice. Chem Biol Interact. 2010;188:246–254.PubMedCrossRef

Zhang Y, Chen H, Yang L. Toll-like receptor 4 participates in gastric mucosal protection through Cox-2 and PGE2. Dig Liver Dis. 2010;42:472–476.PubMedCrossRef

Fan J. TLR cross-talk mechanism of hemorrhagic shock-primed pulmonary neutrophil infiltration. Open Crit Care Med J. 2010;2:1–8.PubMedCrossRef

Wang J, Lu H, Hu X, et al. Nuclear factor translocation and acute anterior uveitis. Mol Vis. 2011;17:170–176.PubMed

Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell. 2008;132:344–362.PubMedCrossRef

10.

Fonin AV, Stepanenko OV, Turoverov KK, Vorob’ev VI. Interaction between non-histone chromatin protein HMGB1 and linker histone H1. Tsitologiia. 2010;52:946–949.PubMed

11.

Lildballe DL, Pedersen DS, Kalamajka R, Emmersen J, Houben A, Grasser KD. The expression level of the chromatin-associated HMGB1 protein influences growth, stress tolerance, and transcriptome in Arabidopsis. J Mol Biol. 2008;384:9–21.PubMedCrossRef

12.

Yang QW, Wang JZ, Li JC, et al. High-mobility group protein box-1 and its relevance to cerebral ischemia. J Cereb Blood Flow Metab. 2010;30:243–254.PubMedCrossRef

13.

Sodhi C, Levy R, Gill R, et al. DNA attenuates enterocyte Toll-like receptor 4-mediated intestinal mucosal injury after remote trauma. Am J Physiol Gastrointest Liver Physiol. 2011;300:G862–G873.PubMedCrossRef

14.

Tsung A, Zheng N, Jeyabalan G, et al. Increasing numbers of hepatic dendritic cells promote HMGB1-mediated ischemia-reperfusion injury. J Leukoc Biol. 2007;81:119–128.PubMedCrossRef

15.

Dhupar R, Klune JR, Evankovich J, et al. Interferon regulatory factor 1 mediates acetylation and release of high mobility group box 1 from hepatocytes during murine liver ischemia-reperfusion injury. Shock. 2011;35:293–301.PubMedCrossRef

16.

Tsung A, Sahai R, Tanaka H, et al. The nuclear factor HMGB1 mediates hepatic injury after murine liver ischemia-reperfusion. J Exp Med. 2005;201:1135–1143.PubMedCrossRef

17.

Loukili N, Rosenblatt-Velin N, Li J, et al. Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo. Cardiovasc Res. 2011;89:586–594.PubMedCrossRef

18.

Xu H, Su Z, Wu J, et al. The alarmin cytokine, high mobility group box 1, is produced by viable cardiomyocytes and mediates the lipopolysaccharide-induced myocardial dysfunction via a TLR4/phosphatidylinositol 3-kinase gamma pathway. J Immunol. 2010;184:1492–1498.PubMedCrossRef

19.

Van Zoelen MA, Yang H, Florquin S, et al. Role of Toll-like receptors 2 and 4, and the receptor for advanced gycation end products (RAGE) in HMGB1 induced inflammation in vivo. Shock. 2008;31:280–284.CrossRef

20.

Yu M, Wang H, Ding A, et al. HMGB1 signals through toll-like receptor (TLR) 4 and TLR2. Shock. 2006;26:174–179.PubMedCrossRef

21.

Lin Q, Yang XP, Fang D, et al. High-mobility group box-1 mediates toll-like receptor 4-dependent angiogenesis. Arterioscler Thromb Vasc Biol. 2011;31:1024–1032.PubMedCrossRef

22.

Zhu XM, Yao YM, Liang HP, et al. High mobility group box-1 protein regulate immunosuppression of regulatory T cells through toll-like receptor 4. Cytokine. 2011;54:296–304.PubMedCrossRef

23.

Wang F, Lu Z, Hawkes M, Yang H, Kain KC, Liles WC. Fas (CD95) induces rapid, TLR4/IRAK4-dependent release of pro-inflammatory HMGB1 from macrophages. J Inflamm (Lond). 2010;7:30.CrossRef

24.

Muhammad S, Barakat W, Stoyanov S, et al. The HMGB1 receptor RAGE mediates ischemic brain damage. J Neurosci. 2008;28:12023–12031.PubMedCrossRef

25.

Volz HC, Kaya Z, Katus HA, Andrassy M. The role of HMGB1/RAGE in inflammatory cardiomyopathy. Semin Thromb Hemost. 2010;36:185–194.PubMedCrossRef

26.

Sterenczak KA, Kleinschmidt S, Wefstaedt P, et al. Quantitative PCR and immunohistochemical analyses of HMGB1 and RAGE expression in canine disseminated histiocytic sarcoma (malignant histiocytosis). Anticancer Res. 2011;31:1541–1548.PubMed

27.

Tian J, Avalos AM, Mao SY, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8:487–496.PubMedCrossRef

28.

Urbonaviciute V, Furnrohr BG, Meister S, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med. 2008;205:3007–3018.PubMedCrossRef

29.

Lv B, Wang H, Tang Y, Fan Z, Xiao X, Chen F. High-mobility group box 1 protein induces tissue factor expression in vascular endothelial cells via activation of NF-kappaB and Egr-1. Thromb Haemost. 2009;102:352–359.PubMed

30.

Yang J, Huang C, Yang J, Jiang H, Ding J. Statins attenuate high mobility group box-1 protein induced vascular endothelial activation: a key role for TLR4/NF-kappaB signaling pathway. Mol Cell Biochem. 2010;345:189–195.PubMedCrossRef

31.

Lee BH, Lee TJ, Jung JW, et al. The role of keratinocyte-derived chemokine in hemorrhage-induced acute lung injury in mice. J Korean Med Sci. 2009;24:775–781.PubMedCrossRef

32.

Aziz M, Jacob A, Matsuda A, et al. Pre-treatment of recombinant mouse MFG-E8 downregulates LPS-induced TNF-alpha production in macrophages via STAT3-mediated SOCS3 activation. PLoS ONE. 2011;6:e27685.PubMedCrossRef

33.

Sharma V, Gilhotra R, Dhingra D, Gilhotra N. Possible underlying influence of p38MAPK and NF-kappaB in the diminished anti-anxiety effect of diazepam in stressed mice. J Pharmacol Sci. 2011;116:257–263.PubMedCrossRef

34.

Gazzieri D, Trevisani M, Springer J, et al. Substance P released by TRPV1-expressing neurons produces reactive oxygen species that mediate ethanol-induced gastric injury. Free Radic Biol Med. 2007;43:581–589.PubMedCrossRef

35.

Fang J, Fang D, Silver PB, et al. The role of TLR2, TRL3, TRL4, and TRL9 signaling in the pathogenesis of autoimmune disease in a retinal autoimmunity model. Invest Ophthalmol Vis Sci. 2010;51:3092–3099.PubMedCrossRef

36.

Murphy TJ, Paterson HM, Kriynovich S, et al. Linking the “two-hit” response following injury to enhanced TLR4 reactivity. J Leukoc Biol. 2005;77:16–23.PubMed

37.

Ehrentraut H, Weber C, Ehrentraut S, et al. The toll-like receptor 4-antagonist eritoran reduces murine cardiac hypertrophy. Eur J Heart Fail. 2011;13:602–610.PubMedCrossRef

38.

Hua F, Ren W, Zhu L. Plasminogen activator inhibitor type-1 deficiency exaggerates LPS-induced acute lung injury through enhancing Toll-like receptor 4 signaling pathway. Blood Coagul Fibrinolysis. 2011;22:480–486.PubMedCrossRef

39.

Fang Y, Hu J. Toll-like receptor and its roles in myocardial ischemic/reperfusion injury. Med Sci Monit. 2011;17:A100–A109.CrossRef

40.

Farmer DG, Ke B, Shen XD, et al. Interleukin-13 protects mouse intestine from ischemia and reperfusion injury through regulation of innate and adaptive immunity. Transplantation. 2011;91:737–743.PubMed

41.

Schmausser B, Andrulis M, Endrich S, et al. Expression and subcellular distribution of toll-like receptors TLR4, TLR5 and TLR9 on the gastric epithelium in Helicobacter pylori infection. Clin Exp Immunol. 2004;136:521–526.PubMedCrossRef

42.

Ortega-Cava CF, Ishihara S, Rumi MA, et al. Strategic compartmentalization of Toll-like receptor 4 in the mouse gut. J Immunol. 2003;170:3977–3985.PubMed

43.

Gao C, Li R, Wang S. Ulinastatin protects pulmonary tissues from lipopolysaccharide-induced injury as an immunomodulator. J Trauma Acute Care Surg. 2012;72:169–176.PubMedCrossRef

44.

Dong L, Li J, Liu Y, Yue W, Luo X. TLR2mAb or/and TLR4mAb increase counts of Lactobacilli and Bifidobacteria in dextran sulfate sodium-induced colitis in mice. J Gastroenterol Hepatol. 2011;27:110–119.CrossRef

45.

Kang JW, Koh EJ, Lee SM. Melatonin protects liver against ischemia and reperfusion injury through inhibition of toll-like receptor signaling pathway. J Pineal Res. 2011;50:403–411.PubMedCrossRef

46.

Peri F, Piazza M, Calabrese V, Damore G, Cighetti R. Exploring the LPS/TLR4 signal pathway with small molecules. Biochem Soc Trans. 2010;38:1390–1395.PubMedCrossRef

47.

Buchholz BM, Bauer AJ. Membrane TLR signaling mechanisms in the gastrointestinal tract during sepsis. Neurogastroenterol Motil. 2010;22:232–245.PubMedCrossRef

48.

Zheng C, Yin Q, Wu H. Structural studies of NF-kappaB signaling. Cell Res. 2011;21:183–195.PubMedCrossRef

49.

Lu YC, Yeh WC, Ohashi PS. LPS/TLR4 signal transduction pathway. Cytokine. 2008;42:145–151.PubMedCrossRef

50.

Wang EL, Qian ZR, Nakasono M, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer. Br J Cancer. 2010;102:908–915.PubMedCrossRef

51.

Obonyo M, Sabet M, Cole SP, et al. Deficiencies of myeloid differentiation factor 88, Toll-like receptor 2 (TLR2), or TLR4 produce specific defects in macrophage cytokine secretion induced by Helicobacter pylori. Infect Immun. 2007;75:2408–2414.PubMedCrossRef

52.

Velayudham A, Hritz I, Dolganiuc A, Mandrekar P, Kurt-Jones E, Szabo G. Critical role of toll-like receptors and the common TLR adaptor, MyD88, in induction of granulomas and liver injury. J Hepatol. 2006;45:813–824.PubMedCrossRef

53.

Cohen MJ, Brohi K, Calfee CS, et al. Early release of high mobility group box nuclear protein 1 after severe trauma in humans: role of injury severity and tissue hypoperfusion. Crit Care. 2009;13:R174.PubMedCrossRef

54.

Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011;29:139–162.PubMedCrossRef

55.

Costello DA, Watson MB, Cowley TR, et al. Interleukin-1 alpha and HMGB1 mediate hippocampal dysfunction in SIGIRR-deficient mice. J Neurosci. 2011;31:3871–3879.PubMedCrossRef

56.

Luan ZG, Zhang H, Yang PT, Ma XC, Zhang C, Guo RX. HMGB1 activates nuclear factor-kappaB signaling by RAGE and increases the production of TNF-alpha in human umbilical vein endothelial cells. Immunobiology. 2010;215:956–962.PubMedCrossRef

57.

Garcia-Arnandis I, Guillen MI, Gomar F, Pelletier JP, Martel-Pelletier J, Alcaraz MJ. High mobility group box 1 potentiates the pro-inflammatory effects of interleukin-1 beta in osteoarthritic synoviocytes. Arthritis Res Ther. 2010;12:R165.PubMedCrossRef

58.

Ha T, Xia Y, Liu X, et al. Glucan phosphate attenuates myocardial HMGB-1 translocation in severe sepsis through inhibiting NF-κB activation. Am J Physiol Heart Circ Physiol. 2011;301:H848–H855.PubMedCrossRef

59.

Agresti A, Lupo R, Bianchi ME, Müller S. HMGB1 interacts differentially with members of the Rel family of transcription factors. Biochem Biophys Res Commun. 2003;302:421–426.PubMedCrossRef

Title: Abnormal Expression of Toll-Like Receptor 4 Is Associated with Susceptibility to Ethanol-Induced Gastric Mucosal Injury in Mice
Authors: Hui-hui Ye
Rong Hua
Le Yu
Ke-jian Wu
Su-juan Fei
Xia Qin
Ying Song
Jun-li Cao
Yong-mei Zhang
Publication date: 01-10-2013
Publisher: Springer US
Published in: Digestive Diseases and Sciences / Issue 10/2013
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-013-2727-5

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