新型免疫抑制剂对三硝基苯磺酸诱导大鼠结肠炎模型的实验研究
摘要
研究背景炎症性肠病(inflammatory bowel diseases,IBD)是一种病因未明的慢性非特异性肠道炎症性疾病。迄今为止,其确切病因和发病机制尚未完全明确。其病因与遗传、免疫、感染、环境等因素有关,其中肠粘膜免疫紊乱在IBD发病机制中具有中心地位。传统药物对IBD疗效不甚理想,寻找新型而有效的药物一直是该领域的研究热点。来氟米特(leflunomide,Lef)是一种新型免疫抑制剂,具有较强细胞和体液免疫抑制作用,在临床上广泛应用于自身免疫性疾病、类风湿性关节炎的治疗,在抑制器官移植的排异反应和狼疮性肾炎中有很好疗效,但其对IBD作用的研究报道较少。
目的观察来氟米特(leflunomide,Lef)对三硝基苯磺酸(trinitrobenzenesulfonic acid,TNBS)诱导结肠炎大鼠的保护作用,并初步探讨其作用机制,为寻找一种治疗炎症性肠病的新药提供一定的实验依据。
方法健康成年雄性(Sprague-Dawley,SD)大鼠60只,清洁级,称重编号,随机分为6组,每组10只,分别设为正常对照组(Nomal,N组)、结肠炎模型组(Model,M组)、Lef低剂量组(low dose Lef,LD组)、Lef中剂量组(Middle dose Lef,MD组)、Lef高剂量组(high dose Lef,HD组)、5-氨基水杨酸(5-aminosalicylic acid,5-ASA)阳性药物对照组(positive,P组)。除正常对照组外,其余5组利用TNBS/乙醇溶液灌肠诱发大鼠结肠炎模型。各组大鼠均在造模后12小时开始给药,N组和M组用0.9%氯化钠2.0ml灌胃,Lef分别按照(1.0,2.0,4.0 mg/kg/D)及5-ASA(100mg/kg/D)用生理盐水配制成2.0ml药液灌胃,每天1次,共14天。连续给药后2周后,深度麻醉处死大鼠,留取标本,分别对大鼠的一般状态、结肠组织黏膜进行大体形态及组织学损伤指数进行评分;免疫组化方法检测结肠组织核因子κ-Bp65(nuclear factor-kappa Bp65,NF-κBp65)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)白介-10(Interleukin-10,IL-10)的表达;ELISA法检测外周血中TNF-α、IL-2、IL-10的含量。
结果与TNBS模型组相比,正常对照组大鼠的疾病活动指数(damage activityindex,DAI)评分、大体形态损伤指数(common morphous damage index,CMDI)及组织学损伤指数(tissue damadge index,TDI)评分显著降低,差异具有统计学意义(P＜0.05),[0.00,0.50±0.28,0.29±0.19 4.5±0.58,5.84±0.37,5.53±0.61P＜0.05];中、高剂量来氟米特(Lef)及5-氨基水杨酸(5-ASA)给药组的DAI、CMDI及TDI的评分显著降低(P＜0.05),[2.08±0.35,0.88±0.37,1.08±0.35,1.84±0.34,1.19±0.20,1.50±0.35,1.93±0.46,1.04±0.15,1.51±0.14,P＜0.05]。与TNBS模型组相比,正常对照组大鼠结肠组织黏膜内NF-κBp65、TNF-α表达显著降低,而IL-10表达水平明显升高,(P＜0.05),[7.91±0.19,184.10±16.19,81.45±20.12,2.13±0.78,68.78±11.16183.36±16.82,P＜0.05];中、高剂量Lef及5-ASA给药组的大鼠结肠组织黏膜内NF-κBp65、TNF-α表达显著降低,而IL-10表达水平明显升高,(P＜0.05),[4.53±0.40,104.18±13.59,148.76±16.53,3.29±0.23,93.06±15.69,165.16±18.98,4.36±0.50,98.31±16.54,156.04±22.96,P＜0.05]。TNBS模型大鼠结肠组织黏膜NF-κBp65的表达以胞核为主,相反正常对照组及治疗组NF-κBp65以胞质表达为主。与TNBS模型组相比,正常对照组大鼠外周血中TNF-α、IL-2的含量减低,IL-10含量显著增加,差异具有统计学意义(P＜0.05),[66.89±7.11,60.18±6.77,26.31±7.79,34.03±6.28,47.09±6.84,55.27±10.02,P＜0.05];中、高剂量Lef及5-ASA给药组大鼠外周血中TNF-α、IL-2的含量减低,IL-10含量显著增加,差异具有统计学意义(P＜0.05),[42.99±5.15,51.52±3.91,51.00±10.01,36.76±4.87,50.56±4.12,53.17±9.90,39.10±5.22,51.53±3.19,50.40±8.55,P＜0.05]。
结论来氟米特对三硝基苯磺酸(TNBS)诱导的结肠炎大鼠有保护作用,其机制可能是通过提高抗炎细胞因子的水平,抑制NF-κB核结合活性,进而降低致炎细胞因子的表达发挥作用。
Background Inflammatory bowel diseases is a chronic relapsing inflammatory disease of the gastrointestinal tract.Its pathogenesis is not completely understood.So far, advances in research have identified the interaction between genetic,infectious, immunological and environmental factors to play role in their pathogenesis.Although their exact cause remains unclear,immunological dysfunction seems to initiate a self-sustaining inflammatory process.Some IBD patients remain refractory to conventional medical treatment,while,in others,the effectiveness of drugs is limited by side-effects.The therapeutic effects of conventional drugs on IBD are not very satisfactory.To seek novel and effective drug is always the hotspot in the study of IBD. Leflunomide is of new immunosuppressant drugs and of cell and humoral immunity immunosuppressive action.Leflunomide is a drug used clinically in the treatment of rheumatoid arthritis and organ transplantation and lupus nephritis and so on Leflunomide treatment of IBD is not to mention.
Objective To investigate the protective effects of leflunomide on trinitrobenzene sulfonic acid(TNBS)-induced colitis in rats and to explore its possible mechanisms.We provide some experimental datas and experiences for seeking novel and effective drug of IBD.
Methods Rat colitis model was induced by TNBS enema.Then the rats were randomly divided into 6 groups:normal control group,model group,5-ASA group(5-ASA,100mg/kg per day)and low-dose、middle-dose and high-dose(1.0,2.0, 4.0mg/kg per day)leflunomide-treated groups.Disease active index(DAI) was observed every day.2 weeks later the mice were killed and their colons were taken out to undergo gistologixal examination.The expression of nuclear factor NF-κBp65 (NF-κBp65) and tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10)in the colonic tissues was detected by immunohistochemistry.The concent rations of blood TNF-αand Interleukin-2 and IL-10 was measured by enzyme linked immunosorbent assay(ELISA).
Results Compared with the TNBS control group,the nomal control group of the damage activity index scores,common morphous damage index and tissue damadge index scores incolonic mucosa was was reduced significantly[0.00,0.50±0.28, 0.29±0.19 4.5±0.58,5.84±0.37,5.53±0.61,P＜0.05].The middle dose Lef group,the high dose Lef group and the 5-ASA group of the DAI scores,CMDI and TDI scores incolonic mucosa was reduced significantly[2.08±0.35,0.88±0.37,1.08±0.35, 1.84±0.34,1.19±0.20,1.50±0.35,1.93±0.46,1.04±0.15,1.51±0.14,P＜0.05]. Compared with the TNBS control group,the the nomal control group of expressions of NF-κBp65,TNF-αin colonic mucosa were also decreased significantly,but IL-10 in colonic mucosa was also increased significantly[7.91±0.19,184.10±16.19,81.45±20.12, 2.13±0.78,68.78±11.16 183.36±16.82,P＜0.05].The middle dose Lef group,the high dose Lef group and the 5-ASA group of expressions of NF-κBp65,TNF-αin colonic mucosa were also decreased significantly,but IL-10 in colonic mucosa was also increased significantly[4.53±0.40,104.1±13.59,148.76±16.53,3.29±0.23, 93.06±15.69,165.16±18.98,4.36±0.50,98.31±16.54,156.04±22.96,P＜0.05].In the tissue sections NF-κBp65 was positive mainly in the nucleus in the TNBS control group, NF-κBp65 was mainly positive in the cytoplasm in normal control group and all treated groups.Compared with the TNBS control group,the nomal control group of the content rations of blood TNF-αand IL-2 was decreased significantly,but the concent rations of blood IL-10 was increased significantly[66.89±7.11,60.18±6.77,26.31±7.79, 34.03±6.28,47.09±6.84,55.27±10.02,P＜0.05].The middle dose lef group,the high dose lef group and the 5-ASA group of the concent rations of blood TNF-αand IL-2 was decreased significantly,but the concent rations of blood IL-10 was increased significantly[42.99±5.15,51.52±3.91,51.00±10.01,36.76±4.87,50.56±4.12, 53.17±9.90,39.10±5.22,51.53±3.19,50.40±8.55,P＜0.05].
Conclusions Leflunomide has noticeable protective effects on TNBS-induced colitis in rats,can increase the level of anti-inflammatory cytokines interleukin-10 and inhibite activation of NF-κB in the colonic mucosa of rat s with colitis and the suppression of proinflammatory cytokines may be one of its main mechanisms.
目的观察来氟米特(leflunomide,Lef)对三硝基苯磺酸(trinitrobenzenesulfonic acid,TNBS)诱导结肠炎大鼠的保护作用,并初步探讨其作用机制,为寻找一种治疗炎症性肠病的新药提供一定的实验依据。
方法健康成年雄性(Sprague-Dawley,SD)大鼠60只,清洁级,称重编号,随机分为6组,每组10只,分别设为正常对照组(Nomal,N组)、结肠炎模型组(Model,M组)、Lef低剂量组(low dose Lef,LD组)、Lef中剂量组(Middle dose Lef,MD组)、Lef高剂量组(high dose Lef,HD组)、5-氨基水杨酸(5-aminosalicylic acid,5-ASA)阳性药物对照组(positive,P组)。除正常对照组外,其余5组利用TNBS/乙醇溶液灌肠诱发大鼠结肠炎模型。各组大鼠均在造模后12小时开始给药,N组和M组用0.9%氯化钠2.0ml灌胃,Lef分别按照(1.0,2.0,4.0 mg/kg/D)及5-ASA(100mg/kg/D)用生理盐水配制成2.0ml药液灌胃,每天1次,共14天。连续给药后2周后,深度麻醉处死大鼠,留取标本,分别对大鼠的一般状态、结肠组织黏膜进行大体形态及组织学损伤指数进行评分;免疫组化方法检测结肠组织核因子κ-Bp65(nuclear factor-kappa Bp65,NF-κBp65)、肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)白介-10(Interleukin-10,IL-10)的表达;ELISA法检测外周血中TNF-α、IL-2、IL-10的含量。
结果与TNBS模型组相比,正常对照组大鼠的疾病活动指数(damage activityindex,DAI)评分、大体形态损伤指数(common morphous damage index,CMDI)及组织学损伤指数(tissue damadge index,TDI)评分显著降低,差异具有统计学意义(P＜0.05),[0.00,0.50±0.28,0.29±0.19 4.5±0.58,5.84±0.37,5.53±0.61P＜0.05];中、高剂量来氟米特(Lef)及5-氨基水杨酸(5-ASA)给药组的DAI、CMDI及TDI的评分显著降低(P＜0.05),[2.08±0.35,0.88±0.37,1.08±0.35,1.84±0.34,1.19±0.20,1.50±0.35,1.93±0.46,1.04±0.15,1.51±0.14,P＜0.05]。与TNBS模型组相比,正常对照组大鼠结肠组织黏膜内NF-κBp65、TNF-α表达显著降低,而IL-10表达水平明显升高,(P＜0.05),[7.91±0.19,184.10±16.19,81.45±20.12,2.13±0.78,68.78±11.16183.36±16.82,P＜0.05];中、高剂量Lef及5-ASA给药组的大鼠结肠组织黏膜内NF-κBp65、TNF-α表达显著降低,而IL-10表达水平明显升高,(P＜0.05),[4.53±0.40,104.18±13.59,148.76±16.53,3.29±0.23,93.06±15.69,165.16±18.98,4.36±0.50,98.31±16.54,156.04±22.96,P＜0.05]。TNBS模型大鼠结肠组织黏膜NF-κBp65的表达以胞核为主,相反正常对照组及治疗组NF-κBp65以胞质表达为主。与TNBS模型组相比,正常对照组大鼠外周血中TNF-α、IL-2的含量减低,IL-10含量显著增加,差异具有统计学意义(P＜0.05),[66.89±7.11,60.18±6.77,26.31±7.79,34.03±6.28,47.09±6.84,55.27±10.02,P＜0.05];中、高剂量Lef及5-ASA给药组大鼠外周血中TNF-α、IL-2的含量减低,IL-10含量显著增加,差异具有统计学意义(P＜0.05),[42.99±5.15,51.52±3.91,51.00±10.01,36.76±4.87,50.56±4.12,53.17±9.90,39.10±5.22,51.53±3.19,50.40±8.55,P＜0.05]。
结论来氟米特对三硝基苯磺酸(TNBS)诱导的结肠炎大鼠有保护作用,其机制可能是通过提高抗炎细胞因子的水平,抑制NF-κB核结合活性,进而降低致炎细胞因子的表达发挥作用。
Background Inflammatory bowel diseases is a chronic relapsing inflammatory disease of the gastrointestinal tract.Its pathogenesis is not completely understood.So far, advances in research have identified the interaction between genetic,infectious, immunological and environmental factors to play role in their pathogenesis.Although their exact cause remains unclear,immunological dysfunction seems to initiate a self-sustaining inflammatory process.Some IBD patients remain refractory to conventional medical treatment,while,in others,the effectiveness of drugs is limited by side-effects.The therapeutic effects of conventional drugs on IBD are not very satisfactory.To seek novel and effective drug is always the hotspot in the study of IBD. Leflunomide is of new immunosuppressant drugs and of cell and humoral immunity immunosuppressive action.Leflunomide is a drug used clinically in the treatment of rheumatoid arthritis and organ transplantation and lupus nephritis and so on Leflunomide treatment of IBD is not to mention.
Objective To investigate the protective effects of leflunomide on trinitrobenzene sulfonic acid(TNBS)-induced colitis in rats and to explore its possible mechanisms.We provide some experimental datas and experiences for seeking novel and effective drug of IBD.
Methods Rat colitis model was induced by TNBS enema.Then the rats were randomly divided into 6 groups:normal control group,model group,5-ASA group(5-ASA,100mg/kg per day)and low-dose、middle-dose and high-dose(1.0,2.0, 4.0mg/kg per day)leflunomide-treated groups.Disease active index(DAI) was observed every day.2 weeks later the mice were killed and their colons were taken out to undergo gistologixal examination.The expression of nuclear factor NF-κBp65 (NF-κBp65) and tumor necrosis factor-α(TNF-α) and interleukin-10(IL-10)in the colonic tissues was detected by immunohistochemistry.The concent rations of blood TNF-αand Interleukin-2 and IL-10 was measured by enzyme linked immunosorbent assay(ELISA).
Results Compared with the TNBS control group,the nomal control group of the damage activity index scores,common morphous damage index and tissue damadge index scores incolonic mucosa was was reduced significantly[0.00,0.50±0.28, 0.29±0.19 4.5±0.58,5.84±0.37,5.53±0.61,P＜0.05].The middle dose Lef group,the high dose Lef group and the 5-ASA group of the DAI scores,CMDI and TDI scores incolonic mucosa was reduced significantly[2.08±0.35,0.88±0.37,1.08±0.35, 1.84±0.34,1.19±0.20,1.50±0.35,1.93±0.46,1.04±0.15,1.51±0.14,P＜0.05]. Compared with the TNBS control group,the the nomal control group of expressions of NF-κBp65,TNF-αin colonic mucosa were also decreased significantly,but IL-10 in colonic mucosa was also increased significantly[7.91±0.19,184.10±16.19,81.45±20.12, 2.13±0.78,68.78±11.16 183.36±16.82,P＜0.05].The middle dose Lef group,the high dose Lef group and the 5-ASA group of expressions of NF-κBp65,TNF-αin colonic mucosa were also decreased significantly,but IL-10 in colonic mucosa was also increased significantly[4.53±0.40,104.1±13.59,148.76±16.53,3.29±0.23, 93.06±15.69,165.16±18.98,4.36±0.50,98.31±16.54,156.04±22.96,P＜0.05].In the tissue sections NF-κBp65 was positive mainly in the nucleus in the TNBS control group, NF-κBp65 was mainly positive in the cytoplasm in normal control group and all treated groups.Compared with the TNBS control group,the nomal control group of the content rations of blood TNF-αand IL-2 was decreased significantly,but the concent rations of blood IL-10 was increased significantly[66.89±7.11,60.18±6.77,26.31±7.79, 34.03±6.28,47.09±6.84,55.27±10.02,P＜0.05].The middle dose lef group,the high dose lef group and the 5-ASA group of the concent rations of blood TNF-αand IL-2 was decreased significantly,but the concent rations of blood IL-10 was increased significantly[42.99±5.15,51.52±3.91,51.00±10.01,36.76±4.87,50.56±4.12, 53.17±9.90,39.10±5.22,51.53±3.19,50.40±8.55,P＜0.05].
Conclusions Leflunomide has noticeable protective effects on TNBS-induced colitis in rats,can increase the level of anti-inflammatory cytokines interleukin-10 and inhibite activation of NF-κB in the colonic mucosa of rat s with colitis and the suppression of proinflammatory cytokines may be one of its main mechanisms.
引文
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1.Gan H,Ouyang Q,Jia D,Xia Q.Activation of nuclear factor-kappaB and its relationship with cytokine gene expression in colonic mucosa of ulcerative colitis patients.Zhonghua Nei Ke Za Zhi,2002;41(4):252-5.
2.Malo MS,Biswas S,Abedrapo MA,et al.The proinflammatory cytokines IL-1 beta and TNF-alpha,inhibit intestinal alkaline phosphatase gene expression.DNA Cell Biol,2006,5(12):684-95.
3.Kwon KH,Murakami A,Hayashi R.,et al.Interleukin-lbeta targets interleukin-6 in progressing dextran sulfate sodium-induced experimental colitis.Biochem Biophys Res Commun,2005,337(2):647-54.
4.Jose Leon A,Garrote JA,Arranz E.Cytokines in the pathogenesis of inflammatory bowel diseases._Med Clin(Bare),2006;127(4):145-52.
5.Van Assche G,Dalle,Noman M,et al.A pilot study on the use of the humanized anti-interleukin-2 receptor antibody daclizumab in active ulcerative colitis.Am J Gastroenterol,2003;98(2):369-76.
6.Daig R,Rogler G,Aschenbrenner E,et al.Hunman intestinal epitheial cells secret interleukin-1 receptor antagonist and intedeukin-8 but not interleukin-1 or interleukin-6.Gut,2000;46(3):350-8.
7. Aleksandra Nielsen A, Nederby Nielsen J, Schmedes A, et al. Saliva interleukin-6 in patients with inflammatory bowel disease. Scand Gastroenterol, 2005; 40(12):1444-8.
8. Mitsuyama K, Tomiyasu N, Suzuki A, et al. A form of circulating interleukin-6 receptor component soluble gp130 as a potential interleukin-6 inhibitor in inflammatory bowel disease. Clin Exp Immunol, 2006; 143(1): 125-31.
9. Reddy KP, Markowitz JE, Ruchelli ED, et al. Lamina propria and circulating interleukin-8 in newly and previously diagnosed pediatric inflammatory bowel disease patients. Dig Dis Sci, 2007; 52(2): 365-72.
10. Danese S, Sans M, de la Motte C, et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology, 2006; 130(7): 2060-73.
11. Arthur M. Barrie III MD. The interleukin-12 family of cytokines: Therapeutic targets for inflammatory disease mediation. Clinical and Applied Immunology Reviews, 2005; 5(4): 225-40.
12. Trinchieri G, Pflanz S, Robert A, et al. The IL-12 Family of Heterodimeric Cytokines New Players in the Regulation of T Cell Responses. Immunity, 2003; 19(5):641-4.
13. Mannon PJ, Fuss IJ, Mayer L, et al. Anti-interleukin-12 antibody for active Crohn's disease. N Engl J Med, 2004; 351(20):2069-79.
14. Kullberg MC, Jankovic D, Feng CG, et al. IL-23 p lays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J Exp Med, 2006; 203(11): 2485 - 94.
15. Holm HU, Brent SM, Sophie H, et al. Differential activity of IL-12 and IL-23 in mucosal and systemic innate immune pathology.Immunity, 2006; 25(2): 309-18.
16. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev,2006;19(3):CD005112.
17. Akobeng AK, Zachos M. Tumor necrosis factor-alpha antibody for induction of remission in Crohn's disease. Cochrane Database Syst Rev, 2004; (1): CD003574.
18. Wang YD, Mao JW. Expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha in ulcerative colitis. World J Gastroenterol, 2007; 13(44): 5926-32.
19. Noguchi M, Hiwatashi N, Hayakawa T, et al. Leukocyte removal filter-passed lymphocytes produce large amounts of interleukin-4 in immunotherapy for inflammatory bowel disease: role of bystander suppression. Ther Apher. 1998; 2(2):109-14.
20. Schreiber S, Fedorak RN, Nielsen OH, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology, 2000,119(6): 1461-72.
21. Asadullah K, SterryW, Volk HD. Interleukin-10 therapy- review of a new approach.Yharmacol Rev, 2003; 55(2): 241-69.
22. Danese S, Semeraro S, Armuzzi A, et al. Biological therapies for inflammatory bowel disease: research drives clinics.Mini Rev Med Chem, 2006; 6(7): 771-84.
23. Hale LP, Greer PK, Trinh CT, et al. Treatment with oral bromelain decreases colonic inflammation in the IL-10-deficient murine model of inflammatory bowel disease. Clin Immunol, 2005; 116(2): 135-42.
24. Mustafa A, El-Medany A, Hagar HH, et al. Ginkgo biloba attenuates mucosal damage in a rat model of ulcerative colitis. Pharmacol Res, 2006, 53(4): 324-30.
25. Menassa R, Du C, Yin ZQ, et al. Therapeutic effectiveness of orally administered transgenic low-alkaloid tobacco expressing human interleukin-10 in a mouse model of colitis. Plant Biotechnol J, 2007; 5(1): 50-9.
26. Whiting CV, Tarlton JF, Bailey M, et al. Abnormal mucosal extracellular matrix deposition is associated with increased TGF-beta receptor-expressing mesenchymal cells in a mouse model of colitis. J Histochem Cytochem, 2003; 51 (9): 1177-89.
27. Monteleone G, Kumberova A, Croft NM, et al. Blocking Smad7 restores TGF-beta 1 signaling in chronic inflammatory bowel disease. J Clin Invest, 2001; 108 (4):601-9.
28. Chowdhury A, Fukuda R, Fukumo S. Growth factor mRNA expression in normal colorectal mucosa and in uninvolved mucosa from ulcerative colitis patients. J Gastroentero 1,1996; 31(3):353-60.
29. Wang YF, Wei B, Ouyang Q. Expression with TGF beta1 in the patients with ulcerative colitis. Sichuan Da Xue Xue Bao Yi Xue Ban, 2005; 36(2): 204-6.
30. Monteleone G, Mann J, Monteleone I, et al. A failure of TGF-bata 1 negative regulation maintains sustained NF-kB activation in gut inflammation. J Biol Chem,2004; 279(6): 3925-32.
31. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 1986; 46(5): 705-16.
32. Chen YG, Zhang C, Chiang SK, et al. Increased nuclear factor-kappa Bp65 immunore activity following retinal ischemia and reperfusion injury in mice. J Neurosci Res, 2003; 72(1): 125-31.
33. Zaninoni A, Imperiali FG, Pasquini C, et al. Cytokine modulation of nuclear factor-kappa B activity in B-chronic lymphocytic leukemia. Exp Hematol, 2003;31(3):185-90.
34. Chen YM, Tu CJ, Hung KY, et al. Inhibition by pentoxifylline of TNF-alpha-stimulated fractalkine production in vascular smooth muscle cells:evidence for mediation by NF-kappa B downregulation. Br J Pharmacol, 2003;138(5): 950-8.
35. Kis A, Yellon DM, Baxter GF. Role of nuclear factor-kappa B activation in acute ischaemia-reperfusion injury in myocardium. Br J Pharmacol, 2003; 138(5): 894-900.
36. Calder VL, Bondeson J, Brennan FM, et al. Antigen-specific T cell down regulation by human dendritic cells following blockade of NF-kappaB. Scand J Immunol, 2003;57(3): 261-70.
37. Ashwood P, Harvey R, Verjee T, et al. Funtional interactions between mucosal IL-1,IL-ra and TGF-betel in ulcerative colitis. Inflamm Res, 2004; 53(2): 53-9.
38. Sawa Y, Oshitani N, Adachi K, et al. Comprehensive analysis of intestinal cytokine messenger RNA profile by real-time quantitative polymerase chain reaction in patient s wit h inflammatory bowel disease.Int J Mol Med,2003;11(2):175-9.
39.甘华田,欧阳钦,贾道全,等.溃疡性结肠炎患者核因子-κB活化与细胞因子基因表达.中华内科杂志,2002;4:252-5.
40.Jian YT,Mai GF,Wang JD,et al.Preventive and therapeutic effects of NF - kappaB inhibitor curcumin in rats colitis induced by trinitrobenzene sulfonic acid.World J Gastroenterol,2005;11(12):1747-52.
41.Dotan I,Rachmilewitz D.Probiotics in inflammatory bowel disease:possible mechanisms of action.Curr Opin Gast roenterol,2005,21(4):426-30.
42.吴礼国,甘华田,欧阳钦,等.核因子κB“诱饵”寡核苷酸对小鼠葡聚糖硫酸钠结肠炎的影响.中华医学杂志,2006;86(20):1394-9.
2.Jaimes H J,Robles-San,Roman M,et al.Rheumatoid arthritis treatment with weekly leflunomide:an open-label study.J Rheumatol,2004,31(2):235-7.
3.Williams JW,Mital D,Chong A,et al.Experiences with leflunomide in solid organ transplantation.Transplantation,2002,73(3):358-66.
4.Remer CF,Weisman MH,Wallace J.Benefits of leflunomide in systemic lupus erythematosus:apilot observational study[J].Lupus,2001,10(7):480-3.
5.Mustala A,El-Medany A,Hagar HH,et al.Ginkgo biloba attenuates mucosal damage in a rat model of ulcrative colitis.Phatmacol Rel,2006,53(4):324-30.
6.Murano M,Maemura K,Hirata I,et al.Therapeutic effect of intracolonically administered nuclear factor kappa B(p65) antisense oligonucleotide on mouse dextran sulphate sodium(DSS)-induced colitis.Clin Exp Immunol,2000,120(1):51-8.
7.王浩,欧阳钦,胡仁伟,等.三硝基苯磺酸的结肠炎动物模型的建立.胃肠病学,2001,6(1):007-10.
8.Koga H,Sakisaka S,Ohishi M,et al.Expression of cyclooxygenase-2 in human hepatocellular carcinoma:relerance to tumor differentiation.Hepatology,1999,29(3):688-9.
9.张晓峰.细胞因子与溃疡性结肠炎.河北医学,2001,7(5):465-7.
10.Indaram AV,Visvalingam V,Locke M,et al.Mucosal cytokine production in radiation-induced proctosigmoiditis compared with inflammatory bowel disease.AM J Gastroenterol,2002,95(5):1221- 5.
11.Gan H,Ouyang Q,Jia D,Xia Q.Activation of nuclear factor-kappaB and its relationship with cytokine gene expression in colonic mucosa of ulcerative colitis patients.Zhonghua Nei Ke Za Zhi,2002;41(4):252- 5.
12.Malo MS,Biswas S,Abedrapo MA,et al.The proinflammatory cytokines,IL-1 beta and TNF-alpha,inhibit intestinal alkaline phosphatase gene expression.DNA Cell Biol,2006,5(12):684-5.
13.Kwon KH,Murakami A,Hayashi R,et al.Interleukin-1 beta targets interleukin-6 in progressing dextran sulfate sodium-induced experimental colitis. Biochem Biophys Res Commun, 2005, 337(2): 647-54.
14. Daig R, Rogler G, Aschenbrenner E, et al. Hunman intestinal epitheial cells secret interleukin-1 receptor antagonist and interleukin-8 but not interleukin-1 or interleukin-6. Gut, 2000; 46(3): 350-8.
15. Aleksandra Nielsen A, Nederby Nielsen J, Schmedes A, et al. Saliva interleukin-6 in patients with inflammatory bowel disease. Scand Gastroenterol, 2005; 40(12):1444-8.
16. Mitsuyama K, Tomiyasu N, Suzuki A, et al. A form of circulating interleukin-6 receptor component soluble gp130 as a potential interleukin-6 inhibitor in inflammatory bowel disease. Clin Exp Immunol, 2006; 143(1): 125-31.
17. Reddy KP, Markowitz JE, Ruchelli ED, et al. Lamina propria and circulating interleukin-8 in newly and previously diagnosed pediatric inflammatory bowel disease patients. Dig Dis Sci, 2007; 52(2): 365-72.
18. Danese S, Sans M, de la Motte C, et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology, 2006; 130(7): 2060-73.
19. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev,2006;19(3):CD005112.
20. Akobeng AK, Zachos M. Tumor necrosis factor-alpha antibody for induction of remission in Crohn's disease. Cochrane Database Syst Rev, 2004; (1): CD003574.
21. Wang YD, Mao JW. Expression of matrix metalloproteinase-1 and tumor necrosis factor-alpha in ulcerative colitis. World J Gastroenterol, 2007; 13(44):5926-32.
22. Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell, 1986; 46(5): 705-16.
23. Chen YG, Zhang C, Chiang SK, et al. Increased nuclear factor-kappa Bp65 immunore activity following retinal ischemia and reperfusion injury in mice. J Neurosci Res, 2003; 72(1): 125-31.
24. Zaninoni A, Imperiali FG, Pasquini C, et al. Cytokine modulation of nuclear factor-kappa B activity in B-chronic lymphocytic leukemia. Exp Hematol, 2003;31(3):185-90.
25. Chen YM, Tu CJ, Hung KY, et al. Inhibition by pentoxifylline of TNF-alpha-stimulated fractalkine production in vascular smooth muscle cells:evidence for mediation by NF-kappa B downregulation. Br J Pharmacol, 2003;138(5): 950-8.
26. Kis A, Yellon DM, Baxter GF. Role of nuclear factor-kappa B activation in acute ischaemia-reperfusion injury in myocardium. Br J Pharmacol, 2003; 138(5):894-900.
27. Calder VL, Bondeson J, Brennan FM, et al. Antigen-specific T cell down regulation by human dendritic cells following blockade of NF-kappaB. Scand J Immunol, 2003;57(3): 261-70.
28. Ashwood P, Harvey R, Verjee T, et al. Funtional interactions between mucosal IL-1, IL-ra and TGF-betel in ulcerative colitis.Inflamm Res,2004;53(2):53-9.
29.Sawa Y,Oshitani N,Adachi K,et al.Comprehensive analysis of intestinal cytokine messenger RNA profile by real-time quantitative polymerase chain reaction in patients wit h inflammatory bowel disease.Int J Mol Med,2003;11(2):175-9.
30.Noguchi M,Hiwatashi N,Hayakawa T,et al.Leukocyte removal filter-passed lymphocytes produce large amounts of interleukin-4 in immunotherapy for inflammatory bowel disease:role of bystander suppression.Ther Apher.1998;2(2):109-14.
31.Schreiber S,Fedorak RN,Nielsen OH,et al.Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease.Crohn's Disease IL-10Cooperative Study Group.Gastroenterology,2000,119(6):1461-72.
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