乙肝肝硬化患者外周血单个核细胞TLR_s的表达及其与血清内毒素的关系
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摘要
背景和目的:内毒素(endotoxin)存在于革兰氏阴性菌的细胞壁,为脂多糖的复合体(lipopolysaccharides,LPS),是革兰氏阴性菌的主要致病成分,细菌的内毒素可以引起内毒素血症。肝硬化患者易并发内毒素血症,而且血液中内毒素水平与肝功能损害程度有关。细菌感染或内毒素所致的炎症反应严重程度与肝硬化病人的天然免疫有关,天然免疫为机体抵御外界病原体的第一道防线。最近有资料显示哺乳动物Toll样受体(toll-like receptors,TLR)参与了由内毒素或其他病原体诱导的细胞内信号转导,其中最关键的是TLR2和TLR4分子。在先天性免疫中,TLR被看作是触发抗微生物反应的关键成分。
因此,本研究的目的在于:1)检测乙肝肝硬化患者外周血单个核细胞(Peripheral blood mononuclear cell,PMBC)TLR2和TLR4 mRNA的表达;2)探索TLR2/TLR4 mRNA表达与血清内毒素及肿瘤坏死因子-α(tumor necrosisfactor-α,TNF-α)的关系,阐明TLR2/TLR4在乙肝肝硬化内毒素血症中的作用。
方法:入选的29例乙肝肝硬化病人均符合2001年病毒性肝炎和肝硬化的诊断标准。除外以下情况:(1)近6周内使用过免疫调节药物;(2)肾功能不全(肌苷＞120 umol/L):(3)合并肿瘤患者;(4)无饮酒史(每日饮酒量少于20g);(5) 6周内无明确感染的或使用抗生素者。肝功能损害程度以Child-Pugh为分级标准。按性别和年龄匹配选择无肝炎病史的健康志愿者10例为正常对照,要求肝功能检测正常,无饮酒史。抽取患者外周静脉血7 ml,其中5 ml留置在经脱酶处理的抗凝管内,采用淋巴细胞分离液(Ficoll)分离得到单个核细胞;采用RT-PCR半定量分析TLR2和TLR4 mRNA水平;另外2ml留置在无内毒素的试管内分离血清,分离的血清储存在-70℃的冰箱里,用鲎试剂定量测定血清内毒素水平和采用放免法测定血清中TNF-α水平。
结果:(1)血清内毒素水平和血清TNF-α水平的变化:与正常对照比较,肝硬化患者血清内毒素水平(分别为0.050EU/ml和0.107EU/ml P＜0.05)和血清TNF-α水平(分别为:1.282pg/ml和2.076pg/ml,P＜0.05)均明显升高;(2)外周血单个核细胞中TLR2和TLR4 mRNA受体的表达:与正常对照比较,肝硬化患者外周血单个核细胞中TLR2的表达明显升高(分别为:0.651和0.923,P＜0.05),且与血清内毒素和TNF-α升高水平呈正相关(r=0.573),而TLR4的表达下调,但差异无统计学意义。
结论:在乙肝肝硬化患者(主要是Child-Pugh B级、Child-Pugh C级)PMBCs的TLR2 mRNA表达水平上调,且与TNF-α的水平呈正相关,但TLR4 mRNA的水平没有变化,表明在肝硬化患者中存在内毒素抵抗现象,可能同时存在革兰氏阳性菌移位通过TLR2介导细胞因子的释放。
Backgrounds & Aims: Endotoxins are complex lipopolysaccharides (LPS), major cell wall components in all Gram-negative bacteria. Bacterial endotoxins can enter the bloodstream, causing endotoxemia. Circulating endotoxin can induce an overwhelming inflammatory host response. The innate immune system (as opposed to the targeted antimicrobial response of the adaptive immune system) is the organism's first line of defense against microbial invasion. Endotoxin may play an important role in alteration immune defenses in cirrhotic patients. Recent data have demonstrated that mammalian Toll-like receptors (TLRs) participate in intracellular signaling initiated by endotoxin/LPS. CD14 has been recognized for many years as the major receptor responsible for the effects of LPS on macrophages, monocytes, and neutrophils. Mutations in some of the TLRs, most prominently TLR4 and TLR2, have been associated with increased susceptibility to infectious diseases, so TLR2 and TLR4 may be involved in mediating endotoxin effects in vivo. TLRs have also emerged as a key component of the innate immune system that triggers antimicrobial responses.
So, the aims of this study is: 1) To study expression of TLR4 and TLR2 mRNA in peripheral blood mononuclear cell (PBMCs) in HBV-associated cirrhosis; 2) To study serum endotoxin and circulating tumor necrosis factor a (TNF-a) levels in cirrhosis, and its relevant to the expression of TLR4 and TLR2 mRNA. Those contributed to comprehensive the role of TLR2 and TLR4 in endotoxemia in HBV-associated cirrhosis.
Methods: 29 patients with HBV-associated cirrhosis and 10 age-matched healthy controls were involved in this study. The diagnosis of HBV-associated cirrhosis was based on the criteria of our country reversed in 2001. The exclusion criteria included(1)Immunomodulatory drug use within the previous 6 weeks,(2)patients with renal insufficiency (serum creatinine>120 uml/L),(3) maiignancy,(4) aicohoi intake history(more than 20 g/d),(5) Infection or antibiotic drug use within the previous 6 weeks. Liver function were evaluated by Child-Pugh Criteria. To address this issue, we isolated peripheral blood monocytes from cirrhotic patients and controls, then we measured (1) circulating endotoxin and TNF-a levels; (2) peripheral blood mononuclear cell (PBMCs) expression of TLR4 and TLR2 by applying the reverse transcriptase polymerase chain reaction (RT-PCR) technique. (3)The data were correlated to serum levels of TNF-α.
Results: Serum Endotoxin(0.050EU/ml VR 0.107EU/ml, P<0.05 ) and TNF-α(1.282pg/ml VR 2.076pg/ml, P<0.05) levels were significantly increased in patients with cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2(0.651 VR 0.923, P<0.05) but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-αlevels.
Conclusions: Up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-αlevels in cirrhosis. These results suggest that expression of TLR2 is altered in PBC monocytes, which appear to be hypersensitive to LPS, resulting in increased secretion of pro-inflammatory cytokines.
因此,本研究的目的在于:1)检测乙肝肝硬化患者外周血单个核细胞(Peripheral blood mononuclear cell,PMBC)TLR2和TLR4 mRNA的表达;2)探索TLR2/TLR4 mRNA表达与血清内毒素及肿瘤坏死因子-α(tumor necrosisfactor-α,TNF-α)的关系,阐明TLR2/TLR4在乙肝肝硬化内毒素血症中的作用。
方法:入选的29例乙肝肝硬化病人均符合2001年病毒性肝炎和肝硬化的诊断标准。除外以下情况:(1)近6周内使用过免疫调节药物;(2)肾功能不全(肌苷＞120 umol/L):(3)合并肿瘤患者;(4)无饮酒史(每日饮酒量少于20g);(5) 6周内无明确感染的或使用抗生素者。肝功能损害程度以Child-Pugh为分级标准。按性别和年龄匹配选择无肝炎病史的健康志愿者10例为正常对照,要求肝功能检测正常,无饮酒史。抽取患者外周静脉血7 ml,其中5 ml留置在经脱酶处理的抗凝管内,采用淋巴细胞分离液(Ficoll)分离得到单个核细胞;采用RT-PCR半定量分析TLR2和TLR4 mRNA水平;另外2ml留置在无内毒素的试管内分离血清,分离的血清储存在-70℃的冰箱里,用鲎试剂定量测定血清内毒素水平和采用放免法测定血清中TNF-α水平。
结果:(1)血清内毒素水平和血清TNF-α水平的变化:与正常对照比较,肝硬化患者血清内毒素水平(分别为0.050EU/ml和0.107EU/ml P＜0.05)和血清TNF-α水平(分别为:1.282pg/ml和2.076pg/ml,P＜0.05)均明显升高;(2)外周血单个核细胞中TLR2和TLR4 mRNA受体的表达:与正常对照比较,肝硬化患者外周血单个核细胞中TLR2的表达明显升高(分别为:0.651和0.923,P＜0.05),且与血清内毒素和TNF-α升高水平呈正相关(r=0.573),而TLR4的表达下调,但差异无统计学意义。
结论:在乙肝肝硬化患者(主要是Child-Pugh B级、Child-Pugh C级)PMBCs的TLR2 mRNA表达水平上调,且与TNF-α的水平呈正相关,但TLR4 mRNA的水平没有变化,表明在肝硬化患者中存在内毒素抵抗现象,可能同时存在革兰氏阳性菌移位通过TLR2介导细胞因子的释放。
Backgrounds & Aims: Endotoxins are complex lipopolysaccharides (LPS), major cell wall components in all Gram-negative bacteria. Bacterial endotoxins can enter the bloodstream, causing endotoxemia. Circulating endotoxin can induce an overwhelming inflammatory host response. The innate immune system (as opposed to the targeted antimicrobial response of the adaptive immune system) is the organism's first line of defense against microbial invasion. Endotoxin may play an important role in alteration immune defenses in cirrhotic patients. Recent data have demonstrated that mammalian Toll-like receptors (TLRs) participate in intracellular signaling initiated by endotoxin/LPS. CD14 has been recognized for many years as the major receptor responsible for the effects of LPS on macrophages, monocytes, and neutrophils. Mutations in some of the TLRs, most prominently TLR4 and TLR2, have been associated with increased susceptibility to infectious diseases, so TLR2 and TLR4 may be involved in mediating endotoxin effects in vivo. TLRs have also emerged as a key component of the innate immune system that triggers antimicrobial responses.
So, the aims of this study is: 1) To study expression of TLR4 and TLR2 mRNA in peripheral blood mononuclear cell (PBMCs) in HBV-associated cirrhosis; 2) To study serum endotoxin and circulating tumor necrosis factor a (TNF-a) levels in cirrhosis, and its relevant to the expression of TLR4 and TLR2 mRNA. Those contributed to comprehensive the role of TLR2 and TLR4 in endotoxemia in HBV-associated cirrhosis.
Methods: 29 patients with HBV-associated cirrhosis and 10 age-matched healthy controls were involved in this study. The diagnosis of HBV-associated cirrhosis was based on the criteria of our country reversed in 2001. The exclusion criteria included(1)Immunomodulatory drug use within the previous 6 weeks,(2)patients with renal insufficiency (serum creatinine>120 uml/L),(3) maiignancy,(4) aicohoi intake history(more than 20 g/d),(5) Infection or antibiotic drug use within the previous 6 weeks. Liver function were evaluated by Child-Pugh Criteria. To address this issue, we isolated peripheral blood monocytes from cirrhotic patients and controls, then we measured (1) circulating endotoxin and TNF-a levels; (2) peripheral blood mononuclear cell (PBMCs) expression of TLR4 and TLR2 by applying the reverse transcriptase polymerase chain reaction (RT-PCR) technique. (3)The data were correlated to serum levels of TNF-α.
Results: Serum Endotoxin(0.050EU/ml VR 0.107EU/ml, P<0.05 ) and TNF-α(1.282pg/ml VR 2.076pg/ml, P<0.05) levels were significantly increased in patients with cirrhosis. Endotoxin levels did not correlate significantly with other parameters. PBMC expression of TLR2(0.651 VR 0.923, P<0.05) but not TLR4 was significantly up-regulated in cirrhosis and correlated significantly with serum TNF-αlevels.
Conclusions: Up-regulation of PBMC expression of TLR2 but not TLR4 occurs in cirrhosis, which implies an important stimulatory role for Gram-positive microbial components but not endotoxin. TLR2 likely contributes to increased circulating TNF-αlevels in cirrhosis. These results suggest that expression of TLR2 is altered in PBC monocytes, which appear to be hypersensitive to LPS, resulting in increased secretion of pro-inflammatory cytokines.
引文
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[21] Fernandez J, Bauer TM, Navasa M, et al. Diagnosis, treatment and prevention of spontaneous bacterial peritonitis. Baillieres Best Pract Res Clin Gastroenterol. 2000;14: 975-990.
[22] Soares-Weiser K, Paul M, Brezis M, et al. Evidence based case report. Antibiotic treatment for-spontaneous bacterial peritonitis.BMJ. 2002 ;12;324:100-102.
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[25] Xu FL, You HB, Li XH, et al. Glycine attenuates endotoxin-induced liver injury by downregulating TLR4 signaling in Kupffer cells. Am J Surg. 2008, 196(1):139-148.
[1]Schmitt H,Wundrack I,Beck S,et al.A third P-domain peptide gene(TFF3),human intestinal trefoil factor,maps to 21q22.3[J].Cytogenet Cell Genet,1996,72:299.
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[1]Schmitt H,Wundrack I,Beck S,et al.A third P-domain peptide gene(TFF3),human intestinal trefoil factor,maps to 21q22.3[J].Cytogenet Cell Genet,1996,72:299.
[2]Seib,T,Blin,N,Hilgert,K,et al.The three human trefoil genes TFF1,TFF2,and TFF3 are located within a region of 55 kb on chromosome 21q22.3[J].Genomics,1997,40:200-202.
[3]Taupin,D,Ooi,O,Yeomans,N,et al.Conserved expression of intestinal trefoil factor in the human colonic adenomacarcinoma sequence [J].Lab Investig,1996,75:25-32.
[4]en JL,Lu YP,Wang L,et al.The expression of TFF1 in normal and impaired gastric mucosa[J].Shi jie Huaren Xiaohua Zazhi,2003,11:1809-10.
[5]Fernandez-Estivariz C,Gu LH,Gu L,et al.Trefoil peptideexpression and goblet cell number in rat intestine:effects of KGF and fasting-refeeding [J].Am J Physiol Regul Integr Comp Physiol,2003,284:564-573.
[6]Dhar DK,WangTC,Tabara H,et al.Expression of cytoplasmic TFF2 is amaker of tumor metasis and negative prognosic factor in gastric cancer[J].Clin Cancer Res,2005,11(18):6472-6478.
[7]Park,W.S.,Oh,R.R.,Park,J.Y.,et al.Mapping of a new target region of allelic loss at 21q22 in primary gastric cancers[J].Cancer Lett,2000,159:15-21.
[8]Chen,Y.H.,Lu,Y.,DeP]aen,I.G.,et al.Transcription factor NF-κB signals antianoikic function of trefoil factor 3 on intestinal epithelial cells[J].Biochem Biophys Res Commun,2000,274:576-582.
[9]Kitajima,S.,S.Takuma,M.Morimoto.Histological analysis of murine colitis induced by dextran sulfate sodium of different molecular weights [J].Exp.Anim,2000,49:9-15.
[10]Schmitt H,Wundrack I,Beck S,et al.A third P-domain peptide aene(TFF3),human intestinal trefoil factor,maps to 21q22.3[J]. Cytogenet Cell Genet, 1996, 72: 299.
[11] Mahida, Y. R., K. Wu, D. P. Jewell. Enhanced production of interleukin 1-beta by mononuclear cells isolated from mucosa with active ulcerative colitis of Crohn's disease[J]. Gut, 1989, 30:835-838.
[12] Liu, D., Chinery, R., Wilding, J., et al. Phosphorylation of-catenin and epidermal growthfactor receptor by intestinal trefoil factor[J]. Lab.Investig, 1997, 77: 557-563.
[13] Williams R, Stamp GW, Gilbert C, et al. pS2 transfection of murine adenocarcinoma cell line 410. 4 enhances dispersed growth pattern in a 3-D collagen gel[J]. J Cell Sci,1996,109:63.
[14] Dignase A, Devaney KL, Lindon H, et al. Ttefoil peptides promote epithelial migration through a transforming growth factor-independent pathy[J]. Clin Invest,1996,94(7): 376-383.
[15] Ribieras S, Tomasetto C, Rio MC. The pS2/TFFl trefoil factor, from basic research to clinical applications[J]. Biochim Biophys Acta, 1998, 1378:F61-F77.
[16] Machado, J. C., Nogueira, A. M., Carneiro, F., et al. Gastric carcinoma exhibits distinct types of cell differentiation: an immuno-histochemical study of trefoil peptides (TFF1 and TFF2) and mucins (MUC1,MUC2,MUC5AC, and MUC6) [J]. J. Pathol, 2000 ,190: 437-443.
[17] Playford RJ, Marchbank T, Chinery R, et al.Human spasmolytic polypeptide is a cytoprotective agent that stimulates cell migration[J].Gastroenterology, 1995, 108: 108-116.
[18] Calnan DP, Westley BR, May FE, et al. The trefoil peptide TFF1 inhibits the growth of the human gastric adenocarcinoma cell line[J]. J Pathol, 1999, 188(3) :312-317.
[19] Farrell JJ, Taupin D, Koh TJ, et al. TFF2/SP-deficient mice show decreased gastric proliferation, increased acid secretion,and increased susceptibility to NSAID injury[J]. J Clin Invest, 2002,109:193-204.