修回日期: 2003-06-01
接受日期: 2003-10-11
在线出版日期: 2004-01-15
核因子-κB(NF-κB)是一类具有多向活性的转录调控因子, 参与多种基因的表达和调控, 在炎症及免疫反应、细胞生长增生、凋亡及感染等方面起着重要作用. 本文重点介绍核因子-κB结构和激活机制, 及其在炎症性肠病中的表达及可能的作用机制; NF-κB抑制剂在炎症性肠病治疗上的应用.
引文著录: 李军华, 于皆平, 何小飞. 核因子-κB与炎症性肠病. 世界华人消化杂志 2004; 12(1): 180-183
Revised: June 1, 2003
Accepted: October 11, 2003
Published online: January 15, 2004
N/A
- Citation: N/A. N/A. Shijie Huaren Xiaohua Zazhi 2004; 12(1): 180-183
- URL: https://www.wjgnet.com/1009-3079/full/v12/i1/180.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v12.i1.180
1986年, Sen和Baltimore[1]首次从B淋巴细胞核提取物中检测到一种转录调控因子, 他能与B淋巴细胞中免疫球蛋白κ轻链基因增强子κB序列(GGGACTTTCC)特异性结合并具有转录调节活性, 故被命名为核因子-κB (nuclear factor-κB, NF-κB). 研究表明, NF-κB同样以无活性的形式广泛存在于其他细胞胞质中; 激活的NF-κB与核内相关基因的κB基序特异结合, 启动或调节相关基因转录, 在免疫和炎症反应、细胞生长、病毒感染及某些疾病急性期反应等方面起着重要作用[2-11].近年研究显示, NF-κB与炎症性肠病(inflammatory bowel disease, IBD)关系密切[12-14]. 本文就此方面作一综述.
NF-κB是NF-κB/Rel家族的一员; 该家族的特征是其肽链亚基均存在约300 bp组成的Rel同源结构域(Rel homology domain, RHD), 内含二聚体化区、DNA结合区和核定位序列, 分别介导Rel蛋白间的二聚体化, Rel蛋白和DNA特异性结合及与IκB(inhibitor of κB)家族成员相互作用. NF-κB/Rel家族包括[15-16] : NF-κB1(p50/p105)、NF-κB2(p52/p100)、p65(RelA)、RelB及C-Rel, 其中大多亚基均可相互结合成同源或异源二聚体, NF-κB最常见的形式是由p50或p52与p65亚基组成的异二聚体[16]. 根据结构和功能等方面的差异Rel家族成员可分为两类: 一类是前体蛋白p105和p100, 其C端具有锚蛋白重复序列(ankyrin repeat motif), 但无反式激活区, 可水解为成熟的p50和p52, p52、p50同源二聚体对转录起抑制作用[17]; 另一类由p65(RelA) 、RelB和C-Rel组成, 其C端含有一个或多个反式激活区, 具有激活基因转录的功能.
静息状态下, NF-κB二聚体与IκB单体偶联, 以无活性的形式存在于细胞质中[18-19]. IκB与NF-κB结合具有以下意义: IκB可与NF-κB亚基的RHD结合, 覆盖核定位序列, 使NF-κB不能发生核易位; 在核内阻止NF-κB与DNA结合; 解离NF-κB与DNA结合的复合体. IκB家族包括IκBα、IκB、IκB /p105、IκBδ/p100、IκBε和Bcl-3[20-22]. 所有已知的IκB均有一由30-33氨基酸组成的重复序列(ankyrin), IκB蛋白籍此与NF-κB的RHD作用, 不同的IκB分子对NF-κB各亚基具有不同的调节活性, 已证实, IκBα与NF-κB的瞬时活化有关, 而IκB则参与了NF-κB的持续活化过程. IκBα对p50-p65异二聚体的抑制作用强于对p50同源二聚体的作用, 而IκB对p50-p65异二聚体的抑制作用强于p50-C Rel复合体, 但IkBα对二者的抑制作用无差异[16].
细胞质中的NF-κB/IκB复合体可被多种因素激活: 如细胞因子(TNF-α、IL-1)、氧化剂、病毒、抗原、佛波醇酯(PMA)、放射线等.其激活机制是一个复杂的过程, 尚未完全阐明, 但至少包括以下步骤: (1) IκB从NF-κB/IκB复合物中解离并降解, 暴露NF-κB的核定位序列; (2)NF-κB易位至核内与特定的κB序列结合. 研究表明, IκB激酶(I-κB kinases, IKKs)在此过程中起着重要的作用. IKKs可特异性磷酸化IκB N端32和36位丝氨酸, 磷酸化的IκB通过泛素连接酶与多个泛素分子结合后发生构象改变, 被26S蛋白酶识别并降解, NF-κB得以释放并移入核内[18,23-27]. NF-κB在核内与新合成的IκB结合后出核, 在胞质中失活.
众多资料显示, 溃疡性结肠炎(UC)和克罗恩(CD)患者肠黏膜组织活检中NF-κB p65亚单位表达明显上调, 且在CD患者中尤为明显[12,28-29]. 免疫组织化学染色表明CD中活化的NF-κB主要定位于黏膜固有层单核细胞(LPMC)及巨噬细胞内, 但黏膜下表皮细胞和内皮细胞中亦可见阳性染色. 双重免疫荧光染色进一步发现活化的NF-κB几乎存在于所有主要的单核细胞亚群中, 包括CD3+ T淋巴细胞、CD20+ B淋巴细胞和CD68+ 的单核吞噬细胞/巨噬细胞. 几乎所有NF-κB的阳性染色都表现在核内, 而仅有少量的NF-κB阳性细胞表现为胞质着色[12,28]. Schreiber et al[12]采用 western blot及电泳迁移率改变法(EMSA)发现在CD和UC患者肠活检组织核提取物中的NF-κB p65蛋白水平明显增高, 但在总的组织提取物中NF-κB p65蛋白水平与正常对照组并无差别, 提示IBD中NF-κB是由胞质转位胞核活化后而发挥生物学功能的.
Thiele et al[28]同时观察了CD患者中NF-κB p50和NF-κB-C Rel亚单位的水平变化. EMSA显示仅有少量的p50从胞质转位至胞核, 而经激素治疗后转位至胞核的p50明显增多; western blot发现转位至核内的NF-κB-C Rel有轻度增高, 同时用抗-C Rel抗体进行的Supershift实验表明C-Rel并非NF-κB的主要成分. Neurath et al[29]的研究表明IBD中p50和C Rel亚单位表达升高, 但p65表达上升更显著, 进一步说明在IBD中起主要作用的是p65亚基; p50在炎症过程中并不活化, 甚至可能参与封闭NF-κB p65的κB结合序列的过程[12].
有关IBD中IkB的报道不一, Yang et al[30]在IL-2缺陷鼠结肠炎发现除NF-κB活性升高外, 还伴有IκBa表达上调, 但大多数人认为IBD患者肠组织中IκB水平与正常人并无不同[12,28]. 实验方法及观察时段的不同是导致结果相异的可能原因之一, 在体外实验中发现TNF-α等刺激后IκB可在短时间(约10 min)内快速反应性地降解或消失, 但60-90 min后再现, 恢复到刺激前水平[12,31].由于IκB和p50是参与NF-κB胞内负反馈调节的主要成分, 这可能提示IBD中NF-κB的自身调节过程存在异常.
CD和UC都是非特异性的慢性肠道炎性疾病, 目前病因、发病机制尚不十分清楚, 可能与感染、免疫异常、遗传及精神等多种因素有关[32-41], 但肠道局部炎性损伤是其病理基础, 以大量炎性细胞浸润和持续存在, 肠道炎性损伤为特征表现. NF-κB通过对细胞因子、黏附分子、趋化(化学)因子及其他炎性递质的调控在IBD炎症反应中起着关键作用.
很多证据均表明了循环和肠道局部细胞因子表达异常是IBD发病的重要机制之一[42-48], 目前发现许多与此密切相关的细胞因子基因启动子或增强子部位均有κB位点, NF-κB在核内与κB序列结合促进多种炎性细胞因子如IL-1、IL-2、IL-6、IL-8、TNF-α及TNF-等的基因转录[2,16]. 在IBD复杂的细胞因子网络失调中, NF-κB活化可能是一中心环节. 已有资料表明IBD中NF-κB活性增高的同时伴有IL-1、IL-6、TNF-α等水平上升[12,28,29]. IL-1、TNF-α可促进NF-κB进一步活化, 后者通过正反馈使IL-1、TNF-α分泌更加增多, 同时使其他细胞因子IL-6、IL-8等表达也增加, 产生级联反应, 使炎症过程得到放大和持续.
有研究表明在炎症性肠病患者肠浆膜组织纤维母细胞中NF-κB和ICAM-1的表达有明显增强[49],Jobin et al[31]在鼠肠上皮细胞系CEI-6细胞中发现TNF-α可以激活NF-κB而促使ICAM-1 mRNA和蛋白表达上升,且采用蛋白酶抑制剂MG-132或ALLN阻断TNF-α诱导的IκB降解过程可以明显降低NF-κB活性和ICAM-1基因表达. NF-κB同时可增强VCAM-1、选择素等黏附分子转录[50-55], 这些黏附分子在白细胞与血管内皮细胞、上皮细胞的稳定黏附, 炎性细胞向炎症部位移行、活化过程中起重要作用.
NF-κB活化还可促进诱生型一氧化氮合酶(iNOS)、环氧化酶-2(COX-2)和5-脂氧化酶等多种酶类表达[56-62].Conner et al[63]发现NF-κB抑制剂MG-341可明显降低肽聚糖诱导的鼠结肠炎中iNOS的上升水平; Nakase et al[64]的研究显示NF-κB抑制剂地塞米松可减轻TNBS诱导的大鼠结肠炎中COX-1、COX-2表达, 提示NF-κB对这些炎性酶类的调节可能是其参与IBD发病的机制之一.
NF-κB同时可增强巨噬细胞炎性蛋白-1α、单核细胞趋化蛋白-1, 3(MCP-1, 3)等其他炎性递质表达[52,65-66], 但NF-κB对这些炎性递质的调控是否参与了IBD炎症损伤过程, 目前的研究尚不能十分肯定.
NF-κB在肠道炎症过程中的中心调控作用, 使其逐渐成为引人注目的新的炎症性肠病治疗靶点. 已证明, 许多IBD临床治疗用药如糖皮质激素、柳氮磺胺吡啶的药理作用均与抑制NF-κB活性有关. 体外实验发现糖皮质激素可通过以下途径抑制NF-κB活化: (1)通过与糖皮质激素受体(GR)结合, 使其活化后在核内与NF-κB p65相互作用, 抑制NF-κB功能. (2)活化的GR激活糖皮质激素反应元件(GRE), 上调IκB表达, 从而影响NF-κB活化[12,28]. 糖皮质激素对NF-κB的抑制正是其发挥广泛抗炎作用的基础. Weber et al[67]证实柳氮磺胺吡啶对NF-κB的抑制作用是通过对IKK-α、IKK-的直接抑制而实现的. 有人发现, 在CD患者肠活检组织LPMC和外周血单核细胞(PBMC)中, 丁酸盐降低前炎性细胞因子IL-1、IL-6等的产量, 同时发现此作用与阻止IκB降解, 抑制NF-κB核转位过程及转录活性有关[68]. 此外, 其他许多免疫抑制剂、抗氧化剂如N-乙酰半胱胺酸(NAC)、抗坏血酸等均可阻断NF-κB活化的信号途径从而抑制NF-κB功能, 但在IBD中的应用和疗效观察尚需进一步的研究.
Neurath et al[69-70]在TNBS诱导和IL-10基因敲除导致的大鼠结肠炎模型中局部给予NF-κB p65亚单位的反义寡核苷酸治疗后发现, 大鼠组织学表现和症状明显改善, 其疗效优于单独使用糖皮质激素, 为临床上运用NF-κB特异性抑制剂治疗IBD提供了实验依据.
随着对IκB激酶在NF-κB活化过程中作用了解的不断深入, 目前很多研究都围绕着如何阻断IκB激酶活化及活化后导致NF-κB激活的信号传导途径这一问题, 以期寻找到新的更安全有效的NF-κB抑制剂. 这些抑制剂具有高度选择性, 可减少或避免传统用药如糖皮质激素的许多毒副作用, 在IBD中具有广阔的治疗前景.但值得注意的是, NF-κB在机体正常免疫反应和细胞生长调节等方面具有重要作用, 如p65缺失可导致胚胎致命性损害及肝脏退行性变; p50或RelB缺失可出现免疫缺陷[16], 过度抑制NF-κB活性可能会导致肝功能衰竭及免疫缺陷.
在IBD患者和动物模型中, NF-κB活性增高, 提示NF-κB与IBD关系密切. 但NF-κB在IBD中的具体作用机制尚不十分清楚, 如NF-κB在IBD中的活化及调节过程, NF-κB活性改变与疾病复发的关系等, 此外, NF-κB对细胞生长和凋亡的调节作用是否参与了IBD的发病过程等也有待进一步的研究. NF-κB在其他免疫性疾病如风湿性关节炎和支气管哮喘中的作用已有广泛研究, 有理由相信, 深入探讨炎症性肠病中NF-κB激活的信号传导途径和自身调节过程, 寻找和研究阻断NF-κB活化的特异性抑制剂, 将为阐明IBD的发病机制及IBD的临床治疗带来新的希望.
编辑: N/A
| 1. | Sen R, Baltimore D. Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell. 1986;46:705-716. [PubMed] [DOI] |
| 2. | Baldwin AS Jr. Series introduction the transcription factor NF-κB and human disease. J Clin Invest. 2001;107:3-6. [PubMed] [DOI] |
| 3. | Matsunaga T, Hokari S, Koyama I, Harada T, Komoda T. NF-kappaB activation in endothelial cells treated with oxidized high-density lipoprotein. Biochem Biophys Res Commun. 2003;303:313-319. [PubMed] [DOI] |
| 4. | Huang WC, Chen JJ, Chen CC. c-Src-dependent tyrosine phosphorylation of IKKbeta is involved in tumor necrosis factor-alpha-induced intercellular adhesion molecule-1 expression. J Biol Chem. 2003;278:9944-9952. [PubMed] [DOI] |
| 5. | Chen YG, Zhang C, Chiang SK, Wu T, Tso MO. Increased nuclear factor-kappaB p65 immunoreactivity following retinal ischemia and reperfusion injury in mice. J Neurosci Res. 2003;72:125-131. [PubMed] [DOI] |
| 6. | Zaninoni A, Imperiali FG, Pasquini C, Zanella A, Barcellini W. Cytokine modulation of nuclear factor-kappaB activity in B-chronic lymphocytic leukemia. Exp Hematol. 2003;31:185-190. [PubMed] [DOI] |
| 7. | Chen YM, Tu CJ, Hung KY, Wu KD, Tsai TJ, Hsieh BS. Inhibition by pentoxifylline of TNF-alpha-stimulated fractalkine production in vascular smooth muscle cells: evidence for mediation by NF-kappaB down-regulation. Br J Pharmacol. 2003;138:950-958. [PubMed] [DOI] |
| 8. | Kis A, Yellon DM, Baxter GF. Role of nuclear factor-kappaB activation in acute ischaemia-reperfusion injury in myocardium. Br J Pharmacol. 2003;138:894-900. [PubMed] [DOI] |
| 9. | Calder VL, Bondeson J, Brennan FM, Foxwell BM, Feldmann M. Antigen-specific T-cell downregulation by human dendritic cells following blockade of NF-kappaB. Scand J Immunol. 2003;57:261-270. [PubMed] [DOI] |
| 10. | Clermont F, Adam E, Dumont JE, Robaye B. Survival pathways regulating the apoptosis induced by tumour necrosis factor-alpha in primary cultured bovine endothelial cells. Cell Signal. 2003;15:539-546. [PubMed] [DOI] |
| 11. | Rakonczay Z, Jarmay K, Kaszaki J, Mandi Y, Duda E, Hegyi P, Boros I, Lonovics J, Takacs T. NF-kappaB activation is detrimental in arginine-induced acute pancreatitis. Free Radic Biol Med. 2003;34:696-709. [PubMed] [DOI] |
| 12. | Schreiber S, Nikolaus S, Hampe J. Activation of nuclear factor kappa B inflammatory bowel disease. Gut. 1998;42:477-484. [PubMed] [DOI] |
| 13. | Neurath MF. Pathogenesis of inflammatory bowel disease: transcription factors in the spotlight. Gut. 1998;42:458-459. [PubMed] [DOI] |
| 14. | Nosti-Escanilla MP, Pena AS. NF-kappa B and inflammatory intestinal diseases. Rev Esp Enferm Dig. 1998;90:113-119. [PubMed] |
| 15. | Glasgow JN, Wood T, Perez-Polo JR. Identification and characterization of nuclear factor kappaB binding sites in the murine bcl-x promoter. J Neurochem. 2000;75:1377-1389. [PubMed] [DOI] |
| 16. | Tak PP, Firestein GS. NF-κB: a key role in inflammatory diseases. J Clin Invest. 2001;107:7-11. [PubMed] [DOI] |
| 17. | Schmid RM, Adler G. NF-kappaB/Rel/IkB: implications in gastrointestinal diseases. Gastroenterology. 2000;118:1208-1228. [PubMed] [DOI] |
| 18. | Ghosh S, May MJ, Kopp EB. NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses. Annu Rev Immunol. 1998;16:225-260. [PubMed] [DOI] |
| 19. | Greten FR, Weber CK, Greten TF, Schneider G, Wagner M, Adler G, Schmid RM. Stat3 and NF-kappaB activation prevents apoptosis in pancreatic carcinogenesis. Gastroenterology. 2002;123:2052-2063. [PubMed] [DOI] |
| 20. | Zhang G, Ghosh S. Toll-like receptor-mediated NF-kappaB activation: a phylogenetically conserved paradigm in innate immunity. J Clin Invest. 2001;107:13-19. [PubMed] [DOI] |
| 21. | May MJ, Ghosh S. Rel/NF-kappa B and I kappa B proteins: an overview. Semin Cancer Biol. 1997;8:63-73. [PubMed] [DOI] |
| 22. | Wang Z, Castresana MR, Detmer K, Newman WH. An IkappaB-alpha mutant inhibits cytokine gene expression and proliferation in human vascular smooth muscle cells. J Surg Res. 2002;102:198-206. [PubMed] [DOI] |
| 23. | Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-kappaB activity. Annu Rev Immunol. 2000;18:621-663. [PubMed] [DOI] |
| 24. | May MJ, Ghosh S. Signal transduction through NF-kappaB. Immunol Today. 1998;19:80-88. [PubMed] [DOI] |
| 25. | Flohe L, Brigelius-Flohe R, Saliou C, Traber MG, Packer L. Redox regulation of NF-kappa B activation. Free Radic Biol Med. 1997;22:1115-1126. [PubMed] [DOI] |
| 26. | Rothwarf DM, Zandi E, Natoli G, Karin M. IKK-gamma is an essential regulatory subunit of the I kappa B kinase complex. Nature. 1998;395:297-300. [PubMed] [DOI] |
| 27. | Nakano H, Shindo M, Sakon S, Nishinaka S, Mihara M, Yagita H, Okumura K. Differential regulation of IkappaB kinases alpha and beta by two upstream kinases, NF-kappaB-inducing kinases and mitogen-activated protein kinases/ERK kinase kinase-1. Proc Natl Acad Sci USA. 1998;95:3537-3542. [PubMed] [DOI] |
| 28. | Thiele K, Bierhaus A, Autschbach F, Hofmann M, Stremmel W, Thiele H, Ziegler R, Nawroth PP. Cell specific effects of glucocorticoid treatment on the NF-kappaBp65/IkappaBalpha system in patients with Crohn's disease. Gut. 1999;45:693-704. [PubMed] [DOI] |
| 29. | Neurath MF, Fuss I, Schurmann G, Pettersson S, Arnold K, Muller-Lobeck H, Strober W, Herfarth C, Buschenfelde KH. Cytokine gene transcription by NF-kappa B family members in patients with inflammatory bowel disease. Ann N Y Acad Sci. 1998;859:149-159. [PubMed] [DOI] |
| 30. | Yang F, de Villiers WJ, Lee EY, McClain CJ, Varilek GW. Increased nuclear factor-kappaB activation in colitis of interleukin-2-deficient mice. J Lab Clin Med. 1999;134:378-387. [PubMed] [DOI] |
| 31. | Jobin C, Hellerbrand C, Licato LL, Brenner DA, Sartor RB. Mediation by NF-kappaB of cytokine induced expression of intercellular adhesion molecule 1(ICAM-1) in an intestinal epithelial cell line, a process blocked by proteasome inhibitors. Gut. 1998;42:779-787. [PubMed] [DOI] |
| 32. | Jiang XL, Cui HF. An analysis of 10218 ulcerative colitis cases in China. World J Gastroenterol. 2002;8:158-161. [PubMed] [DOI] |
| 33. | Xu G, Tian KL, Liu GP, Zhong XJ, Tang SL, Sun YP. Clinical significance of plasma D-dimer and von Willebrand factor levels in patients with ulcer colitis. World J Gastroenterol. 2002;8:575-576. [PubMed] [DOI] |
| 34. | Cui HF, Jiang XL. Treatment of corticosteroid-resistant ulcerative colitis with oral low molecular weight heparin. World J Gastroenterol. 1999;5:448-450. [PubMed] [DOI] |
| 35. | Wu HG, Zhou LB, Shi DR, Liu SM, Liu HR, Zhang BM, Chen HP, Zhang LS. Morphological study on colonic pathology in ulcerative colitis treated by moxibustion. World J Gastroenterol. 2000;6:861-865. [PubMed] [DOI] |
| 36. | MacDonald TT, Monteleone G, Pender SL. Recent developments in the immunology of inflammatory bowel disease. Scand J Immunol. 2000;51:2-9. [PubMed] [DOI] |
| 37. | Salupere R. Inflammatory bowel disease in Estonia: a prospective epidemiologic study 1993-1998. World J Gastroenterol. 2001;7:387-388. [PubMed] [DOI] |
| 38. | Stoyanova II, Gulubova MV. Mast cells and inflammatory mediators in chronic ulcerative colitis. Acta Histochem. 2002;104:185-192. [PubMed] [DOI] |
| 39. | Kirsner JB. Historical origins of current IBD concepts. World J Gastroenterol. 2001;7:175-184. [PubMed] [DOI] |
| 40. | Xia B, Guo HJ, Crusius J, Deng CS, Meuwissen S, Pena A. In vitro production of TNF-alpha, IL-6 and sIL-2R in Chinese patients with ulcerative colitis. World J Gastroenterol. 1998;4:252-255. [PubMed] [DOI] |
| 41. | Funakoshi K, Sugimura K, Anezaki K, Bannai H, Ishizuka K, Asakura H. Spectrum of cytokine gene expression in intestinal mucosal lesions of Crohn's disease and ulcerative colitis. Digestion. 1998;59:73-78. [PubMed] [DOI] |
| 42. | Monteleone G, MacDonald TT. Manipulation of cytokines in the management of pa tients with inflammatory bowel disease. Ann Med. 2000;32:552-560. [PubMed] [DOI] |
| 43. | Brown KA, Back SJ, Ruchelli ED, Markowitz J, Mascarenhas M, Verma R, Piccoli DA, Baldassano RN. Lamina propria and circulating interleukin-6 in newly diagnosed pediatric inflammatory bowel disease patients. Am J Gastroenterol. 2002;97:2603-2608. [PubMed] [DOI] |
| 44. | Sasaki M, Jordan P, Houghton J, Meng X, Itoh M, Joh T, Alexander JS. Transfection of IL-10 expression vectors into endothelial cultures attenuates alpha 4 beta 7-dependent lymphocyte adhesion mediated by MAdCAM-1. BMC Gastroenterol. 2003;3:3. [PubMed] [DOI] |
| 45. | Tamura K, Fukuda Y, Sashio H, Takeda N, Bamba H, Kosaka T, Fukui S, Sawada K, Tamura K, Satomi M. IL18 polymorphism is associated with an increased risk of Crohn's disease. J Gastroenterol. 2002;37:111-116. [PubMed] [DOI] |
| 46. | Ito H, Hirotani T, Yamamoto M, Ogawa H, Kishimoto T. Anti-IL-6 receptor monoclonal antibody inhibits leukocyte recruitment and promotes T-cell apoptosis in a murine model of Crohn's disease. J Gastroenterol. 2002;37:56-61. [PubMed] [DOI] |
| 47. | Schmidt C, Marth T, Wittig BM, Hombach A, Abken H, Stallmach A. Interleukin-12 antagonists as new therapeutic agents in inflammatory bowel disease. Pathobiology. 2002;70:177-183. [PubMed] [DOI] |
| 48. | Lochner M, Forster I. Anti-interleukin-18 therapy in murine models of inflammatory bowel disease. Pathobiology. 2002;70:164-169. [PubMed] [DOI] |
| 49. | Brannigan AE, Watson RW, Beddy D, Hurley H, Fitzpatrick JM, O'Connell PR. Increased adhesion molecule expression in serosal fibroblasts isolated from patients with inflammatory bowel disease is secondary to inflammation. Ann Surg. 2002;235:507-511. [PubMed] [DOI] |
| 50. | Viita H, Sen CK, Roy S, Siljamaki T, Nikkari T, Yla-Herttuala S. High expression of human 15-lipoxygenase induces NF-kappaB-mediated expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and T-cell adhesion on human endothelial cells. Antioxid Redox Signal. 1999;1:83-96. [PubMed] [DOI] |
| 51. | Kaur J, Woodman RC, Ostrovsky L, Kubes P. Selective recruitment of neutrophils and lymphocytes by thrombin: a role for NF-kappaB. Am J Physiol Heart Circ Physiol. 2001;281:H784-795. [PubMed] |
| 52. | Minami T, Aird WC. Thrombin stimulation of the vascular cell adhesion molecule-1 promoter in endothelial cells is mediated by tandem nuclear factor-kappa B and GATA motifs. J Biol Chem. 2001;276:47632-47641. [PubMed] [DOI] |
| 53. | Dichtl W, Ares MP, Jonson AN, Jovinge S, Pachinger O, Giachelli CM, Hamsten A, Eriksson P, Nilsson J. Linoleic acid-stimulated vascular adhesion molecule-1 expression in endothelial cells depends on nuclear factor-kappaB activation. Metabolism. 2002;51:327-333. [PubMed] [DOI] |
| 54. | Weber KS, Draude G, Erl W, de Martin R, Weber C. Monocyte arrest and transmigration on inflamed endothelium in shear flow is inhibited by adenovirus-mediated gene transfer of IkappaB-alpha. Blood. 1999;93:3685-3693. [PubMed] |
| 55. | Kokura S, Wolf RE, Yoshikawa T, Granger DN, Aw TY. Molecular mechanisms of neutrophil-endothelial cell adhesion induced by redox imbalance. Circ Res. 1999;84:516-524. [PubMed] [DOI] |
| 56. | Dijkstra G, Moshage H, Jansen PL. Blockade of NF-kappaB activation and donation of nitric oxide: new treatment options in inflammatory bowel disease? Scand J Gastroenterol Suppl. 2002;236:37-41. [PubMed] [DOI] |
| 57. | Rafiee P, Johnson CP, Li MS, Ogawa H, Heidemann J, Fisher PJ, Lamirand TH, Otterson MF, Wilson KT, Binion DG. Cyclosporine A enhances leukocyte binding by human intestinal microvascular endothelial cells through inhibition of p38 MAPK and iNOS. Paradoxical proinflammatory effect on the microvascular endothelium. J Biol Chem. 2002;277:35605-35615. [PubMed] [DOI] |
| 58. | Grisham MB, Pavlick KP, Laroux FS, Hoffman J, Bharwani S, Wolf RE. Nitric oxide and chronic gut inflammation: controversies in inflammatory bowel disease. J Investig Med. 2002;50:272-283. [PubMed] [DOI] |
| 59. | Naito Y, Takagi T, Ishikawa T, Handa O, Matsumoto N, Yagi N, Matsuyama K, Yoshida N, Yoshikawa T, Kotake Y. alpha-Phenyl-N-tert-butylnitrone provides protection from dextran sulfate sodium-induced colitis in mice. Antioxid Redox Signal. 2002;4:195-206. [PubMed] [DOI] |
| 60. | Cavicchi M, Whittle BJ. Regulation of induction of nitric oxide synthase and the inhibitory actions of dexamethasone in the human intestinal epithelial cell line, Caco-2: influence of cell differentiation. Br J Pharmacol. 1999;128:705-715. [PubMed] [DOI] |
| 61. | Schwertschlag US, Trepicchio WL, Dykstra KH, Keith JC, Turner KJ, Dorner AJ. Hematopoietic, immunomodulatory and epithelial effects of interleukin-11. Leukemia. 1999;13:1307-1315. [PubMed] [DOI] |
| 62. | Weaver SA, Russo MP, Wright KL, Kolios G, Jobin C, Robertson DA, Ward SG. Regulatory role of phosphatidylinositol 3 -kinase on TNF-alpha-induced cyclooxygenase 2 expression in colonic epithelial cells. Gastroenterology. 2001;120:1117-1127. [PubMed] [DOI] |
| 63. | Conner EM, Brand S, Davis JM, Laroux FS, Palombella VJ, Fuseler JW, Kang DY, Wolf RE, Grisham MB. Proteasome inhibition attenuates nitric oxide synthase expression, VCAM-1 transcription and the development of chronic colitis. J Pharmacol Exp Ther. 1997;282:1615-1622. [PubMed] |
| 64. | Nakase H, Okazaki K, Tabata Y, Uose S, Ohana M, Uchida K, Nishi T, Debreceni A, Itoh T, Kawanami C. An oral drug delivery system targeting immune-regulating cells ameliorates mucosal injury in trinitrobenzene sulfonic acid-induced colitis. J Pharmacol Exp Ther. 2001;297:1122-1128. [PubMed] |
| 65. | Brueckmann M, Marx A, Martin Weiler H, Liebe V, Lang S, Kaden JJ, Zieger W, Borggrefe M, Huhle G, Konstantin Haase K. Stabilization of monocyte chemoattractant protein-1-mRNA by activated protein C. Thromb Haemost. 2003;89:149-160. [PubMed] |
| 66. | Fietta AM, Morosini M, Meloni F, Bianco AM, Pozzi E. Pharmacological analysis of signal transduction pathways required for mycobacterium tuberculosis-induced IL-8 and MCP-1 production in human peripheral monocytes. Cytokine. 2002;19:242-249. [PubMed] [DOI] |
| 67. | Weber CK, Liptay S, Wirth T, Adler G, Schmid RM. Suppression of NF-kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta. Gastroenterology. 2000;119:1209-1218. [PubMed] [DOI] |
| 68. | Segain JP, Raingeard de la Bletiere D, Bourreille A, Leray V, Gervois N, Rosales C, Ferrier L, Bonnet C, Blottiere HM, Galmiche JP. Butyrate inhibits inflammatory responses through NFkappaB inhibition: implications for Crohn's disease. Gut. 2000;47:397-403. [PubMed] [DOI] |
| 69. | Neurath MF, Pettersson S, Meyer zum Buschenfelde KH, Strober W. Local administration of antisense phosphorothioate oligonucleotides to the p65 subunit of NF-kappa B abrogates established experimental colitis in mice. Nat Med. 1996;2:998-1004. [PubMed] [DOI] |
| 70. | Neurath MF, Pettersson S. Predominant role of NF-kappa B p65 in the pathogenesis of chronic intestinal inflammation. Immunobiology. 1997;198:91-98. [PubMed] [DOI] |