Intestinal mucosal injury induced by obstructive jaundice is associated with activation of TLR4/TRAF6/NF-κB pathways


Autoři: Xiaopeng Tian aff001;  Huimin Zhao aff002;  Zixuan Zhang aff001;  Zengcai Guo aff002;  Wen Li aff001
Působiště autorů: Medical School of Chinese PLA, Beijing, China aff001;  Department of Gastroenterology, Xingtai People’s Hospital, Xingtai, Hebei, China aff002;  Department of Gastroenterology and Hepatology, the First Medical Center of Chinese PLA General Hospital, Beijing, China aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223651

Souhrn

Objectives

To investigate the role of TLR4/TRAF6/NF-κB pathways in intestinal mucosal injury induced by obstructive jaundice (OJ).

Methods

A total of 100 male C57BL/6J mice were randomly assigned to two groups: (I) sham operation (SH); (II) OJ. The mice were sacrificed before operation and on the 1st, 3rd, 5th and 7th day after operation. The blood and terminal ileum were simultaneously collected under the aseptic condition for further detection.

Results

In the SH group, TLR4 protein and mRNA rarely expressed in the intestinal mucosa of the mice and there were no significant differences at different time points (p>0.05). By contrast, in the OJ group TLR4 protein (0.12±0.06, 0.16±0.08, 0.27±0.10, 0.35±0.12 and 0.41±0.13, respectively) and mRNA (0.49±0.19, 0.62±0.23, 0.98±0.32, 1.42±0.41 and 1.72±0.49, respectively) increased gradually with the extension of time (p<0.05). Also in the OJ group, the levels of DAO and endotoxin in plasma as well as the expressions of NF-κB and caspase-3 increased gradually with the extension of time, showing positive correlation with the expression of TLR4 (p<0.05).

Conclusions

The expression of TLR4 was significantly up-regulated in the distal ileum of mice with OJ. Activation of the TLR4/TRAF6/NF-κB pathways was involved in the occurrence and development of intestinal mucosal injury and endotoxemia in mice with OJ.

Klíčová slova:

Apoptosis – Cytoplasm – Cytoplasmic staining – Endotoxins – Gastrointestinal tract – Ileum – Inflammation – Toll-like receptors


Zdroje

1. Natalskiy AA, Tarasenko SV, Zaytsev OV, Peskov OD, Lunkov IA. The diagnositic and treatment algorithm for patients with obstructive jaundice syndrome. Eksp Klin Gastroenterol. 2015;7: 38–45.

2. Kononenko SN, Limonchikov SV. The diagnostics of the obstructive jaundice and possibilities to improve the efficacy of its miniinvasive treatment. Khirurgiia (Mosk). 2011; 9: 4–10.

3. Iida A, Yoshidome H, Shida T, Kimura F, Shimizu H, Ohtsuka M, et al. Does prolonged biliary obstructive jaundice sensitize the liver to endotoxemia? Shock. 2009;31: 397–403. doi: 10.1097/SHK.0b013e31818349ea 18665046

4. Jones C, Badger SA, Black JM, McFerran NV, Hoper M, Diamond T, et al. The use of antiendotoxin peptides in obstructive jaundice endotoxemia. Eur J Gastroenterol Hepatol. 2012; 24: 248–254. doi: 10.1097/MEG.0b013e32834dfb8c 22246330

5. Arancibia SA, Beltran CJ, Aguirre IM, Silva P, Peralta AL, Malinarich F, et al. Toll-like receptors are key participants in innate immune responses. Biol Res. 2007;40: 97–112. doi: 10.4067/s0716-97602007000200001 18064347

6. Płóciennikowska A, Hromada-Judycka A, Borzęcka K, Kwiatkowska K. Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling. Cell Mol Life Sci. 2015;72: 557–581. doi: 10.1007/s00018-014-1762-5 25332099

7. Tanaka K. Expression of Toll-like receptors in the intestinal mucosa of patients with inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2008;2: 193–196. doi: 10.1586/17474124.2.2.193 19072354

8. Kawai T, Akira S. Antiviral signaling through pattern recognition receptors. J Biochem. 2007;141(2): 137–145. doi: 10.1093/jb/mvm032 17190786

9. Uematsu S, Akira S. Toll-like receptors and type I interferons. J Biol Chem. 2007;282: 15319–15323. doi: 10.1074/jbc.R700009200 17395581

10. Li W, Chung SC. An improved rat model of obstructive jaundice and its reversal by internal and external drainage. J Surg Res. 2001;101: 4–15. doi: 10.1006/jsre.2001.6240 11676548

11. Ca likülekci M, Pata C, Apa DD, Dirlik M, Tamer L, Yaylak F, et al. The effect of N-acetylcysteine (NAC) on liver and renal tissue inducible nitric oxide synthase (iNOS) and tissue lipid peroxidation in obstructive jaundice stimulated by lipopolysaccharide (LPS). Pharmacol Res. 2004;49: 227–238. doi: 10.1016/j.phrs.2003.09.013 14726217

12. Penkov N. Pathogenetic mechanisms in biliary obstruction. Khirurgiia (Sofi ia). 2003;59: 39–45.

13. Kononenko SN, Limonchikov SV. The diagnostics of the obstructive jaundice and possibilities to improve the efficacy of its miniinvasive treatment. Khirurgiia (Mosk). 2011; (9): 4–10.

14. Iida A, Yoshidome H, Shida T, Kimura F, Shimizu H, Ohtsuka M, et al. Does prolonged biliary obstructive jaundice sensitize the liver to endotoxemia? Shock. 2009; 31: 397–403. doi: 10.1097/SHK.0b013e31818349ea 18665046

15. Jones C, Badger SA, Black JM, McFerran NV, Hoper M, Diamond T, et al. The use of antiendotoxin peptides in obstructive jaundice endotoxemia. Eur J Gastroenterol Hepatol. 2012; 24: 248–254. doi: 10.1097/MEG.0b013e32834dfb8c 22246330

16. Prado IB, Santos MH, Lopasso FP, Iriya K, Laudanna AA. Cholestasis in a murine experimental model: Lesions include hepatocyte ischemic necrosis. Rev Hosp Clin Fac Med Sao Paulo. 2003;58: 27. 12754587

17. Zhang J B, Du X G, Zhang H, Li ML, Xiao G, Wu J, et al. Breakdown of the gut barrier in patients with multiple organ dysfunction syndrome is attenuated by continuous blood purification: effects on tight junction structural proteins. Int J Artif Organs. 2010;33: 5–14. 20127656

18. Zhao Y, Qin G, Sun Z, Che D, Bao N, Zhang X. Effects of soybean agglutinin on intestinal barrier permeability and tight junction protein expression in weaned piglets. Int J Mol Sci. 2011;12: 8502–8512. doi: 10.3390/ijms12128502 22272087

19. Fei L, Xu K. Zhikang Capsule ameliorates dextran sodium sulfate-induced colitis by inhibition of inflammation, apoptosis, oxidative stress and MyD88-dependent TLR4 signaling pathway. J Ethnopharmacol. 2016;192: 236–247. doi: 10.1016/j.jep.2016.07.055 27452656

20. Hering NA, Fromm M, Schulzke JD. Determinants of colonic barrier function in inflammatory bowel disease and potential therapeutics. The Journal of Physiology. 2012;590: 1035–1044. doi: 10.1113/jphysiol.2011.224568 22219336

21. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11: 373–384. doi: 10.1038/ni.1863 20404851

22. Kamdar K, Nguyen V, DePaolo RW. Toll-like receptor signaling and regulation of intestinal Immunity. Virulence. 2013;4: 207–212. doi: 10.4161/viru.23354 23334153

23. Blasius AL, Beutler B. Intracellular toll-like receptors. Immunity. 2010;32: 305–315. doi: 10.1016/j.immuni.2010.03.012 20346772

24. Wang X, Wu L, Wu K, Zhang R, Dong Y. Roles of endotoxin-related signaling molecules in the progression of acute necrotizing pancreatitis in mice. Pancreas. 2005;31: 251–257. doi: 10.1097/01.mpa.0000175179.62916.17 16163057

25. Li Z, Xia X, Zhang S, Zhang A, Bo W, Zhou R. Up-regulation of Toll-like receptor 4 was suppressed by emodin and baicalin in the setting of acute pancreatitis. Biomed Pharmacother. 2009;63: 120–128. doi: 10.1016/j.biopha.2008.01.003 18343629

26. Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET, Arditi M. Decreased expression of Toll-like receptor 4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J Immunol. 2001;167: 1609–1616. doi: 10.4049/jimmunol.167.3.1609 11466383

27. Cario E, Podolsky DK. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3(TLR3) and TLR4 in inflammatory bowel disease. In-fect Immun. 2000;68: 7010–7017.

28. Ortega-Cava CF, Ishihara S, Runi MA, Kawashima K, Ishimura N, Kazumori H, et al. Strategic compart mentalization of Toll-like receptor4 in the mouse gut. J Immunol. 2003;170: 3977–3985. doi: 10.4049/jimmunol.170.8.3977 12682225

29. Otte JM, Cario E, Podolsky DK. Mechanisms of cross hyporesponsiveness to Toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology. 2004; 126: 1054–1070. doi: 10.1053/j.gastro.2004.01.007 15057745

30. Singh JC, Craickshank SM, Newton DJ, Wakenshaw L, Graham A, Lan J, et al. Toll-like receptor mediated responses of primary intestinal epithelial cells during the development of colitis. Am J Physiol Gastrointest Liver Physiol. 2005;288: 514–524.

31. Hausmann M, kiessling S, Mestermann S, Webb G, Spöttl T, Andus T, et al. Toll-like receptors 2 and 4 are upregulated during intestinal inflammation. Gastroenterology. 2002;122: 1987–2000. doi: 10.1053/gast.2002.33662 12055604

32. Noreen M, Shah MA, Mall SM, Choudhary S, Hussain T, Ahmed I, et al. TLR4 polymorphisms and disease susceptibility. Inflamm Res. 2012; 61: 177–188. doi: 10.1007/s00011-011-0427-1 22277994

33. Inagaki T, Moschetta A, Lee YK, Peng L, Zhao G, Downes M, et al. Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc Natl Acad Sci USA. 2006;103: 3920–3925. doi: 10.1073/pnas.0509592103 16473946

34. Richardson WM, Sodhi CP, Russo A, Siggers RH, Afrazi A, Gribar SC, et al. Nucleotide-binding oligomerization domain-2 inhibits toll-like receptor-4 signaling in the intestinal epithelium. Gastroenterology. 2010;139: 904–917. doi: 10.1053/j.gastro.2010.05.038 20580721

35. Liu SZ, He XM, Zhang X. schemic Preconditioning-Induced SOCS-1 Protects Rat Intestinal Ischemia Reperfusion Injuryvia Degradation of TRAF6. Dig Dis Sci. 2017;62: 105–114. doi: 10.1007/s10620-016-4277-0 27538408

36. Pasparakis M. Regulation of tissue homeostasis by NF-kappa B signalling: implications for inflammatory diseases. Nature reviews Immunology. 2009; 9: 778–88. doi: 10.1038/nri2655 19855404

37. Li H, Lin X. Positive and negative signaling components involved in TNFalpha-induced NF-kappa B activation. Cytokine. 2008; 41: 1–8. doi: 10.1016/j.cyto.2007.09.016 18068998

38. Jiang L, Zhang Y. The role of nuclear factor kappa B activation in barrier of gastrointestine by sepsis in rats. Applied Journal of General Practice. 2007;2: 97–98.

39. Wullaert A, Bonnet MC, Pasparakis M. NF-kappa B in the regulation of epithelial homeostasis and inflammation. Cell Res. 2011; 21: 146–158. doi: 10.1038/cr.2010.175 21151201

40. Covert MW, Leung TH, Gaston JE, Baltimore D. Achieving stability of lipopolysaccharide-induced NF-kappa B activation. Science. 2005; 309: 1854–1857. doi: 10.1126/science.1112304 16166516

41. Paterson RL, Glalley HF, Dhillon JK, Webster NR. Increased nuclear Factor kappa B activation in critically ill patients who die. Crit Care Med. 2000;28: 1047–1051. doi: 10.1097/00003246-200004000-00022 10809280

42. Bouma G, Strober W. The immunological and genetic basis of inflammatory bowel disease. Nat Rev Immunol. 2003;3: 521–533. doi: 10.1038/nri1132 12876555

43. Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem. 2011; 286: 31263–31271. doi: 10.1074/jbc.M111.238147 21771795

44. Webb LV, Ley SC, Seddon B. TNF activation of NF-κB is essential for development of single-positive thymocytes. J Exp Med. 2016;213: 1399–1407. doi: 10.1084/jem.20151604 27432943

45. Koh SJ, Kim JM, Kim IK, Ko SH, Kim JS. Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer. J Gastroenterol Hepatol.2014;29: 502–510. doi: 10.1111/jgh.12435 24716225

46. Xavier R J, Podolsky D K. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007; 448: 427–434. doi: 10.1038/nature06005 17653185

47. Chen K, Xie W, Luo B, Xiao W, Teitelbaum DH, Yang H, et al. Intestinal mucosal barrier is injured by BMP2/4 via activation of NF-κB signals after ischemic reperfusion. Mediators Inflamm. 2014;2014: 901530. doi: 10.1155/2014/901530 25132736

48. Suzuki T, Yoshinaga N, Tanabe S. Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium. J Biol Chem. 2011;286: 31263–31271. doi: 10.1074/jbc.M111.238147 21771795


Článek vyšel v časopise

PLOS One


2019 Číslo 10