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RELP, a novel human REG-like protein with up-regulated expression in inflammatory and metaplastic gastrointestinal mucosa

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 11-20页

作者： Kämäräinen, M Heiskala, K Knuutila, S Heiskala, M Winqvist, O Andersson, LC Univ Helsinki Dept Pathol Haartman Inst FIN-00014 Helsinki Finland Univ Helsinki Cent Hosp Diagnost Lab Helsinki Finland Univ Helsinki Dept Med Genet Helsinki Finland RW Johnson Pharmaceut Res & Dev San Diego CA USA

2We screened expressed sequence tag databases for genes with up-regulated expression in inflammatory bowel diseases. A gene encoding a regenerating protein (REG)-like protein called RELP was identified and characterized. The relp gene encodes a major transcript of 1518 nucleotides, and two truncated splice variants. Unlike the reg genes, which form a cluster in chromosome 2, relp maps to chromosome 1p12-13.1. The predicted translation product is a 158-amino acid preprotein, showing 43% to 47% similarity to the REG proteins. It contains a 22-amino acid signal peptide, and a conserved calcium-dependent carbohydrate-recognition domain. Complementary DNA for the orthologous mouse gene was also cloned. The RELP protein is constitutively expressed in epithelial neuroendocrine cells of the small intestine and in parietal cells of the gastric mucosa. An up-regulated expression of RELP was seen in epithelial cells of inflammatory mucosa in ulcerative colitis and Crohn's disease, in regenerating epithelial borders of gastric ulcers, and in metaplastic epithelium in the antrum and the esophagus. Our findings suggest that RELP might be involved in inflammatory and metaplastic responses of the gastrointestinal epithelium.

关键词：碱基序列染色体人 1对数据库遗传学表达的序列标记胃黏膜/细胞学胃黏膜/病理学胃黏膜/生理学原位杂交荧光炎性肠疾病/遗传学炎性肠疾病/代谢肠黏膜/细胞学肠黏膜/病理学肠黏膜/生理学外源凝集素类 C型化生分子序列数据神经组织蛋白质类/遗传学神经组织蛋白质类/代谢蛋白质生物合成序列比对组织分布肿瘤细胞培养的增量调节/生理学动物人类小鼠

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The transmembrane form of the CX3CL1 chemokine fractalkine is expressed predominantly by epithelial cells in vivo

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AMERICAN JOURNAL OF PATHOLOGY 2001年第3期158卷 855-866页

作者： Lucas, AD Chadwick, N Warren, BF Jewell, DP Gordon, S Powrie, F Greaves, DR Univ Oxford Sir William Dunn Sch Pathol Oxford OX1 3RE England John Radcliffe Hosp Nuffield Dept Surg Oxford OX3 9DU England John Radcliffe Hosp Dept Cellular Pathol Oxford OX3 9DU England Radcliffe Infirm Gastroenterol Unit Oxford OX2 6HE England

Fractalkine (CX3CL1) is synthesized as a type I transmembrane protein. Its unique CX3C chemokine domain is attached to a 241-amino acid mucin stalk, a 19-amino acid transmembrane domain, and a 37-amino acid intracellular domain of unknown function. A soluble form of fractalkine can be generated by proteolytic cleavage at the base of the mucin stalk. Novel monoclonal and polyclonal antibodies that specifically recognize only the amino- or carboxyl-terminal ends of the human fractalkine molecule have revealed that epithelial cells are the predominant cell type expressing transmembrane forms of fractalkine in human skin, the tonsil, and the large intestine. Using these specific anti-fractalkine reagents we do not detect high-level expression of fractalkine on endothelial cells in normal or inflamed colon samples obtained from patients with Crohn's disease or ulcerative colitis. In contrast to previous reports we do not detect fractalkine expression by Langerhans cells or immature dendritic cells in mucosal-associated lymphoid tissues in vivo. We show that the reagent used in previous studies, an anti-fractalkine N-terminal peptide antisera, cross-reacts with human CD84. Finally we discuss potential roles for fractalkine in constitutive leukocyte trafficking based on its observed pattern of expression in epithelia.

关键词：腺癌/代谢抗体/免疫学抗体特异性抗原 CD/免疫学 CHO细胞细胞系趋化因子 CX3C 趋化因子 CXC/免疫学趋化因子 CXC/代谢结肠/代谢结直肠肿瘤/代谢仓鼠亚科交叉反应表皮/代谢上皮细胞/代谢炎性肠疾病/代谢角蛋白质类/代谢膜糖蛋白类膜蛋白质类/免疫学膜蛋白质类/代谢肽类/免疫学蛋白质亚型/代谢扁桃体/代谢肿瘤细胞培养的动物人类

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The intestinal mucus layer from patients with inflammatory bowel disease harbors high numbers of bacteria compared with controls

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GASTROENTEROLOGY 1999年第5期117卷 1089-1097页

作者： Schultsz, C van den Berg, FM ten Kate, FW Tytgat, GNJ Dankert, J Univ Amsterdam Acad Med Ctr Dept Med Microbiol NL-1105 AZ Amsterdam Netherlands Univ Amsterdam Acad Med Ctr Dept Pathol NL-1105 AZ Amsterdam Netherlands Univ Amsterdam Acad Med Ctr Dept Gastroenterol NL-1105 AZ Amsterdam Netherlands

Background & Aims: Whether the bacterial flora contributes to the pathogenesis of inflammatory bower disease (IBD) by increased penetration in mucus, increased adherence to epithelial cells, or invasion of the epithelium is unknown. We therefore studied the spatial distribution of bacteria in the mucosa of rectal biopsy specimens from patients with IBD and from controls. Methods: Rectal biopsy specimens from 19 patients with IBD and from 14 controls were studied by using nonradioactive ribosomal RNA in situ hybridization. Total mucosal surface length examined for each patient was measured, and the number of bacteria visualized was estimated semiquantitatively. Results: No bacteria were observed in biopsy specimens from 10 controls (71%) and 6 IBD patients (32%) (P = 0.04;odds ratio, 5.42;95% confidence interval, 1.23-23.9). IBD rectal specimens contained significantly more bacteria than control samples (P = 0.004). Bacteria were localized within the mucus layer but did not adhere to the epithelial cells and were not present within the lamina propria. There was no correlation between the numbers of bacteria present and either the degree of inflammation or the use of antiinflammatory agents or sulfasalazine compounds. Conclusions: The intestinal mucus in IBD patients is less protective against the endogenous microflora than in controls, resulting in increased association of luminal bacteria with the mucus layer.

关键词：细菌/分离和提纯活组织检查结肠/微生物学结肠/病理学集落计数微生物回肠/微生物学回肠/病理学原位杂交炎性肠疾病/代谢炎性肠疾病/微生物学炎性肠疾病/病理学肠黏膜/代谢黏蛋白类/代谢黏液/代谢黏液/微生物学直肠/微生物学直肠/病理学参考值染色与标记人类

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Mucosal cytokine production in radiation-induced proctosigmoiditis compared with inflammatory bowel disease

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AMERICAN JOURNAL OF GASTROENTEROLOGY 2000年第5期95卷 1221-1225页

作者： Indaram, AVK Visvalingam, V Locke, M Bank, S Albert Einstein Coll Med Div Gastroenterol Long Isl Jewish Med Ctr New Hyde Pk NY 11040 USA

OBJECTIVE: We measured the mucosal levels of interleukin 1 beta (IL-1 beta), IL-2, IL-6, and IL-X in affected segments of radiation-induced proctosigmoiditis and compared these with the levels in normal controls and inflammatory bowel disease (IBD) patients. METHODS: Thirteen patients with histologically proven radiation proctosigmoiditis, 32 patients with active ulcerative colitis (UC), 35 patients with Crohn's disease, and 15 normal subjects undergoing routine colonoscopy were included in the study. All patients underwent colonoscopy and mucosal biopsies were obtained from both diseased and normal-appearing areas. Mucosal levels of IL-1 beta, IL-2, IL-6, and IL-8 were determined by solid-phase enzyme-linked immunosorbent assay (ELISA) using the Quantikine method (R&D Systems, Minneapolis, MN). All the data were statistically analyzed using Student's t test. RESULTS: The mucosal levels of IL-2, IL-6, and IL-8 were significantly higher in both diseased segments (5.62 +/- 0.13, 1.60 +/- 0.31, and 21.45 +/- 4.03 pg/ml, respectively) and normal-appearing segments (3.83 +/- 0.78, 1.36 +/- 0.34, and 13.45 +/- 3.18 pg/mg) in the radiation proctitis group compared to those of normal control subjects (1.74 +/- 0.23, 0.67 +/- 0.09, and 4.99 +/- 1.39 pg/mg). These differences were statistically significant. (p < 0.05). In the UC group, IL-1 beta, IL-6, and IL-8 levels in diseased segments were 4.98 +/- 0.53, 2.22 +/- 0.28, and 88.85 +/- 8.05 pg/mg, respectively. In Crohn's disease patients, IL-1 beta, 1L-6, and a-X levels were 5.45 +/- 0.93, 2.88 +/- 0.58, and 61.68 +/- 10.02 pg/mg, respectively. All these levels were significantly higher (p < 0.05) compared with IL-1 beta, IL-6, and IL-8 levels from normal segments of IBD patients. Compared with the radiation proctitis patients, the levels of IL-6 and IL-8 were significantly higher in the LED group. CONCLUSIONS: The mucosal levels of IL-2, IL-6, and IL-8 were significantly higher in both diseased and normal segments of colon

关键词：结肠炎溃疡性/代谢结肠/代谢 Crohn病/代谢酶联免疫吸附测定炎性肠疾病/代谢白细胞介素类/生物合成肠黏膜/代谢直肠结肠炎/病因学直肠结肠炎/代谢辐射损伤/代谢人类

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Mononuclear leukocytes bind to specific hyaluronan structures on colon mucosal smooth muscle cells treated with polyinosinic acid:: Polycytidylic acid -: Inter-α-trypsin inhibitor is crucial to structure and function

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AMERICAN JOURNAL OF PATHOLOGY 2003年第1期163卷 121-133页

作者： de la Motte, CA Hascall, VC Drazba, J Bandyopadhyay, SK Strong, SA Cleveland Clin Fdn Lerner Res Inst Dept Colorectal Surg Cleveland OH 44195 USA Cleveland Clin Fdn Lerner Res Inst Dept Immunol Cleveland OH 44195 USA Cleveland Clin Fdn Dept Biomed Engn Cleveland OH 44195 USA Cleveland Clin Fdn Imaging Core Lab Cleveland OH 44195 USA

Inflammatory bowel disease (IBD) is a chronic disorder whose etiology is linked to triggering events, including viral infections, that lead to immunoregulatory dysfunction in genetically susceptible people. Characteristic pathological changes include increased mononuclear leukocyte influx into the intestinal mucosa as well as mucosal smooth muscle cell (M-SMC) hyperplasia. Virus infection or viral mimic [polyinosinic acid:polycytidylic acid (polyI:C)] treatment of human colon M-SMCs in vitro increases cell surface hyaluronan (HA), and nonactivated mononuclear leukocytes bind to virus-induced RA structures by interactions that involve the HA-binding receptor CD44. In this study, confocal microscopy reveals increased HA on poly I:C-treated M-SMC surfaces within 3 hours, arrayed in coat-like structures. By 17 hours, novel, lengthy cable structures are evident, and these are primarily responsible for mediating leukocyte adhesion. Immunohistochemical staining demonstrates components of the inter-alpha-trypsin inhibitor (IalphaI) complex in both coat-like and cable structures. M-SMCs co-treated with polyI:C and a polyclonal. antibody to IalphaI display RA in coats but with diminished cables, and they bind significantly fewer leukocytes than M-SMCs;treated with polyI:C alone. Western blot data suggest that heavy chains of IalphaI are specifically associated with cable structures. Staining of tissue sections from patients with IBD demonstrates the presence of RA in inflamed colon tissue, and shows that HA-associated IalphaI staining increases in the mucosa of inflamed IBD specimens compared to noninflamed sections from the same patient, establishing a probable link between the observations in vitro and the progression of the inflammatory process in IBD.

关键词：甲种球蛋白类/免疫学甲种球蛋白类/代谢抗病毒药/药理学细胞黏附/生理学细胞培养的硫酸软骨素蛋白聚糖类/代谢结肠/解剖学和组织学结肠/代谢结肠/病理学透明质酸/代谢炎症/代谢炎性肠疾病/免疫学炎性肠疾病/代谢炎性肠疾病/病理学肠黏膜/细胞学肠黏膜/代谢外源凝集素类 C型白细胞单核/代谢显微镜检查荧光肌细胞平滑肌/药物作用肌细胞平滑肌/代谢聚肌胞苷酸/药理学多功能蛋白聚糖类人类

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Subclinical gut inflammation in spondyloarthropathy patients is associated with upregulation of the E-cadherin/catenin complex (vol 59, pg 211, 2000)

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ANNALS OF THE RHEUMATIC DISEASES 2000年第5期59卷 400-400页

作者： Demetter, P Department of Pathology University Hospital University of Gent University Hospital 6 Blok A De Pintelaan 185 9000 Gent Belgium.

OBJECTIVE-Previously an upregulation of E-cadherin and its associated molecules α-catenin, β-catenin and plakoglobin has been demonstrated in clinically overt inflammatory bowel disease (IBD). The aim of this study was to investigate the expression of the E-cadherin/catenin complex in subclinically inflamed bowel mucosa from spondyloarthropathy (SpA) patients. METHODS-Ileal and colonic biopsy specimens from 19 SpA patients with subclinical inflammatory gut lesions and from seven controls were stained with monoclonal antibodies against E-cadherin, β-catenin and plakoglobin and a polyclonal antibody against α-catenin. E-cadherin mRNA was detected using a riboprobe. Inflammation was histologically classified into acute, chronic active and chronic quiescent forms. RESULTS-In acute and chronic active bowel inflammation of SpA patients, upregulation of the E-cadherin/catenin glycoprotein complex could be observed. Chronic lesions in a quiescent state did not show such an upregulation. Furthermore, chronic inflammation was associated with an increase in E-cadherin mRNA. CONCLUSIONS-As some of the SpA patients with subclinical gut inflammation develop IBD, upregulation of the E-cadherin/catenin complex in inflamed bowel mucosa from SpA patients may point to early cellular changes in the development of IBD. However, at present it cannot be excluded that increased E-cadherin/catenin complex expression is a bystander phenomenon of active inflammation.

关键词：急性病钙黏着糖蛋白类/代谢慢性病细胞支架蛋白质类/代谢桥粒斑蛋白质类免疫酶技术原位杂交炎性肠疾病/病因学炎性肠疾病/代谢脊柱炎/并发症脊柱炎/代谢反式激活因子类增量调节 α连环素 β连环素 γ连环素成年人儿童女(雌)性人类男(雄)性中年人

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Nutrition and inflammatory bowel disease

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GASTROENTEROLOGY CLINICS OF NORTH AMERICA 1999年第2期28卷 423-+页

作者： Han, PD Burke, A Baldassano, RN Rombeau, JL Lichtenstein, GR Univ Penn Sch Med Philadelphia PA 19104 USA Hosp Univ Penn Sch Med Dept Surg Div Gastrointestinal Surg Philadelphia PA 19104 USA Hosp Univ Penn Sch Med Dept Pediat Philadelphia PA 19104 USA Childrens Hosp Philadelphia Div Gastroenterol & Nutr Philadelphia PA 19104 USA

This article reviews the nutritional aspects of inflammatory bowel disease (IBD) including the mechanisms and manifestations of malnutrition and the efficacy of nutritional therapies. Nutrient deficiencies in patients with IBD occur via several mechanisms and may complicate the course of the disease. Nutritional status is assessed by clinical examination and the use of nutritional indices such as the Subjective Global Assessment of nutritional status. Nutritional intervention may improve outcome in certain individuals;however, because of the costs and complications of such therapy, careful selection is warranted, especially in patients presumed to need parenteral nutrition.

关键词：消炎药/治疗应用结肠炎溃疡性/并发症结肠炎溃疡性/膳食疗法 Crohn病/并发症 Crohn病/膳食疗法能量摄取鱼油/治疗应用炎性肠疾病/并发症炎性肠疾病/膳食疗法炎性肠疾病/药物疗法炎性肠疾病/代谢营养评价营养障碍/膳食疗法营养障碍/病因学营养障碍/代谢胃肠外营养全患病率前瞻性研究随机对照试验(主题) 甾类人类

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Altered IgG₄ renal clearance in patients with inflammatory bowel diseases.: Evidence for a subclinical impairment of protein charge renal selectivity

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NEPHROLOGY DIALYSIS TRANSPLANTATION 2000年第4期15卷 498-501页

作者： Monteleone, G Cristina, G Parrello, T Morano, S Biancone, L Pietravalle, P Sagratella, E Doldo, P Luzza, F Di Mario, U Pallone, F DipartimentodiMedicinaSperimentaleeClinica Universita'diCatanzaroandCattedradiEndocrinologiaUniversita'diRoma'LaSapienza'RomaItaly.

Background.A loss of intestinal glycosaminoglycans (GAGs) has been shown in inflammatory bowel diseases (IBD). Since GAGs are involved in the regulation of renal protein filtration and GAGs disruption is associated with anionic proteinuria, we examined whether changes in the selectivity of renal protein filtration occur in IBD. *** 46 patients with IBD (17 with Crohn's disease (CD), and 29 with ulcerative colitis (UC)) and 21 healthy subjects, urine and serum samples were obtained. Albumin, total IgG and IgG4 clearances were measured using sensitive methods. Serum p-ANCA and TNF-α were tested. *** IgG4 clearance was 0.041 ml/ min/10^-3 in patients with UC and 0.10 ml/ min/10^-3 in CD patients, both significantly higher than in controls (0.03 ml/min/10^-3) (P<0.03). IgG4 clearance was above the upper normal limit in 9/17 CD (53%) and in 10/29 UC (34.5%). Eighteen of 19 patients showing abnormal IgG4 clearance were taking mesalazine. In patients on maintenance oral mesalazine, IgG4 clearance was higher than that in patients off treatment (0.12 vs 0.03 ml/min/10^-3, P=0.04). No clinical/laboratory sign of renal dysfunction was documented in patients with altered IgG4 clearance and maintained on mesalazine treatment. *** protein charge permselectivity is impaired in 40% of patients with IBD with no overt proteinuria. Our data suggest that altered IgG4 clearance may represent a subclinical marker of renal involvement in IBD.

关键词：抗体抗中性白细胞胞质/血液生物学标记/血液生物学标记/尿肾小球滤过率/药物作用葡糖氨基聚糖类/尿免疫球蛋白G/尿炎性肠疾病/并发症炎性肠疾病/药物疗法炎性肠疾病/代谢肾/药物作用肾/代谢氨水杨酸/投药和剂量氨水杨酸/治疗应用疾病严重程度指数肿瘤坏死因子α/代谢人类

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Systemic levels of free 5-aminosalicylic acid depend on the nature of the 5-aminosalicyclic acid derivative and not on disease activity or extent in patients with inflammatory bowel disease

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IRISH JOURNAL OF MEDICAL SCIENCE 1999年第4期168卷 228-232页

作者： Mahmud, N Weir, DG Kelleher, D Trinity Coll Dept Clin Med Dublin Ireland

Introduction Several new derivatives of sulphasalazine that make use of its active moiety, 5-aminosalicylic acid (5-ASA), have been introduced for the treatment of inflammatory bowel disease (IBD). In rats short term intravenous administration of 5-ASA has been associated with nephrotoxicity. A number of cases of nephrotoxicity have been reported recently in IBD patients taking oral maintenance treatment with 5-ASA compounds. Objective To study the urinary and serum levels of acetylated 5-ASA (Ac-5-ASA) and the unacetylated 5-ASA (5-ASA) in patients with IBD maintained on sulphasalazine, olsalazine and mesalazine (pH dependent release form). We also sought correlation between levels of 5-ASA, clinical disease activity and extent of disease. Methods We studied 79 patients (male, n=30; female, n=49) with established IBD [ulcerative colitis (UC), n=48; Crohn’s disease (CD), n=31], 72 maintained on 5-ASA compounds (sulphasalazine = 27; olsalazine = 28; mesalazine = 17) and 7 patients were receiving no medication. Urinary and serum analysis of 5-ASA was performed by high performance liquid chromatography (HPLC). Clinical disease activity was quantified using simple index of Harvey and Bradshaw. Results Patients receiving mesalazine had significantly higher levels of serum free 5-ASA compared to those who were receiving olsalazine and sulphasalazine (mesalazine mean ± SEM; range; 2.84 ±1.21 (0.00–16.00) vs olsalazine 0.45 ±0.18 (0.00–16.20); μmol/L; p< 0.04; sulphasalazine 0.37 ±0.25 (0.00?3.74); p< 0.03). Similarly levels of urinary free 5-ASA were significantly higher in patients maintained on mesalazine compared to those on olsalazine or sulphasalazine (mesalazine 219 ±80.43 (0.00?1050) vs olsalazine 33.3 ± 17.23 (0.00–317) μmol/L; p< 0.01; and sulphasalazine 15 ±8.86 (0.00–192); p< 0.05). However, no significant difference was observed in the levels of urinary free 5-ASA between olsalazine and sulphasalazine. No significant difference was observed in the levels

关键词：氨基水杨酸类/副作用氨基水杨酸类/血液氨基水杨酸类/代谢氨基水杨酸类/治疗应用氨基水杨酸类/尿消炎药非甾类/代谢消炎药非甾类/治疗应用色谱法高压液相胃肠病用药/代谢胃肠病用药/治疗应用炎性肠疾病/药物疗法炎性肠疾病/代谢氨水杨酸/代谢氨水杨酸/治疗应用回归分析柳氮磺胺吡啶/代谢柳氮磺胺吡啶/治疗应用青少年成年人老年人女(雌)性人类男(雄)性中年人

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NF-κB in IBD:: Does binding to DNA imply transcriptional activity?

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GASTROENTEROLOGY 1999年第6期116卷 1504-1505页

作者： Andresen, L Eugen-Olsen, J Perner, A Rask-Madsen, J Univ Copenhagen Hvidovre Hosp Clin Res Unit Copenhagen Denmark Univ Copenhagen Hvidovre Hosp Dept Gastroenterol Copenhagen Denmark

GASTROENTEROLOGY 1999;116:1504-1505

关键词： DNA/代谢炎性肠疾病/遗传学炎性肠疾病/代谢 NF-κB/代谢转录遗传/生理学人类

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