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Background & Aims: Basic fibroblast growth factor (bFGF) is a promising therapeutic agent for various diseases. It remains unclear, however, whether bFGF is effective for the treatment of inflammatory bowel disease. The aim of this study was to examine the efficacy of bFGF on 2 experimental murine colitis models and to investigate its molecular mechanisms. Methods: We evaluated the effects of human recombinant bFGF (hrbFGF) on mice with dextran sulfate sodium (DSS)-induced colitis and mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis as well as normal mice. Body weight, survival rate, and histologic findings of the colonic tissues were examined. Gene expression of tumor necrosis factor (TNF)-α, cyclooxygenase (COX)-2, transforming growth factor (TGF)-β, mucin 2 (MUC2), intestinal trefoil factor (ITF), and vascular endothelial growth factor (VEGF) in the colonic tissues was determined. The proliferation activity of hrbFGF on the colonic epithelium was evaluated by immunohistochemistry. Results: Rectal administration of hrbFGF ameliorated DSS-induced colitis in a dose-dependent manner. Gene expression of TNF-α was significantly reduced in the colonic tissues of mice with DSS-induced colitis treated with hrbFGF, whereas MUC2 and ITF messenger RNA expression was up-regulated. Rectal administration of hrbFGF significantly improved the survival rate of mice with TNBS-induced colitis and partially ameliorated colitis. hrbFGF significantly increased the number of Ki-67-positive cells in the colonic epithelium of normal mice, and up-regulated the gene expression of COX-2, TGF-β, MUC2, ITF, and VEGF in the colonic tissues. Conclusions: Rectal administration of bFGF might be a promising option for the treatment of inflammatory bowel disease.

Background & Aims: Interleukin (IL)-7 is a critical cytokine in the development of T and B cells and is involved in gastrointestinal pathophysiology.The aim of this study was to investigate the involvement of IL-7 receptor (IL-7R) signaling in Helicobacter -induced gastritis. Methods: C57BL/6 mice (n = 40) were inoculated with H.felis .Twenty mice were injected intraperitoneally with neutralizing IL-7R antibody (A7R34) every seventh day for 3 months.Histology, serum anti– H.felis antibody, and gene expression of IL-7, IL-7R, and proinflammatory cytokines in the gastric mucosa were evaluated. Results: Seventeen of 20 (85%) infected mice without A7R34 developed severe atrophic gastritis, whereas there was no gastritis in A7R34-treated infected mice.There was no difference in the serum levels of anti– H.felis antibody between the 2 groups.IL-7, IL-7R, IL-1α, tumor necrosis factor α, and interferon γ messenger RNA expressions were up-regulated in control infected mice, whereas only IL-7 messenger RNA was up-regulated in A7R34-treated infected mice.Immunohistochemistry indicated positive cytoplasmic staining of IL-7 in the gastric epithelial cells. Conclusions: These data suggest a critical role for IL-7 receptor signaling in the development of Helicobacter -induced gastritis in mice. GASTROENTEROLOGY 2001;121:329-336

Background Indomethacin is one of the group of nonsteroidal anti-inflammatory drugs, which often cause gastric mucosal injury as a side effect. Infiltration and activation of inflammatory cells, production of proinflammatory cytokines and chemokines, generation of reactive oxygen species, and activation of apoptotic signaling are involved in the pathogenesis of indomethacin-induced gastric injury. We examined whether sake yeast-derived thioredoxin (a small redox-active protein with anti-oxidative activity and various redox-regulating functions) reduced indomethacin-induced gastric injury.

Objectives: IgG4-related autoimmune pancreatitis (AIP) is a new clinical entity of pancreatic disorder. There are immunologic and histological abnormalities, including increased serum IgG4 levels and the infiltration of lymphocytes and IgG4-positive plasmacytes. However, the role of IgG4 is unclear. Recently, regulatory T cells (Tregs) were reported to contribute to the development of various autoimmune diseases as well as in B cell shifting to IgG4producing plasmacytes. For this report, we studied regulatory T cells in the pancreas by immunohistochemistory and ICOS+ Tregs and IL-10 producing cells in the peripheral blood lymphocytes by flowcytometry. Methods: We recruited 44 patients with IgG4-related AIP. For comparison, we recruited 37 patients with other pancreatic diseases and 27 healthy subjects as controls. We studied infiltrating cells in the pancreas by immunohistochemistry, and analyzed ICOS+ Tregs and IL-10+ Tregs in the peripheral blood by flow cytometry. Results: The ratio of Foxp3-positive cells to infiltrated mononuclear cells (Foxp3/Mono) in AIP patients (0.091 ± 0.023) was significantly higher than in patients with alcoholic chronic pancreatitis (0.012 ± 0.003; p

The densities (pA/pF) of IA in anti-NGF treated rats was 95.8±25 (n=13) as compared with 33.76±6.5 in vehicle-treated rats (n=9; P

Background & Aim: Autoimmune pancreatitis (AIP) is a newly recognized pancreatic disorder. Patients with AIP have several immunologic and histologic abnormalities specific to the disease, including increased levels of serum IgG4 and storiform fibrosis with infiltration of lymphocytes and IgG4-positive plasmacytes in the involved organs. Among the involved organs showing extrapancreatic lesions, bile duct is the most common, exhibiting sclerosing cholangitis (IgG4-SC). However, the role of IgG4 is unclear in the pancreas and involved organs. Recently, it has been reported that regulatory T cells (Tregs) are involved in both the development of various autoimmune diseases and the shift of B-cell toward IgG4 producing plasmacytes. For this report, we analyzed the infiltrated Tregs and IgG4-positive plasma cells in the pancreas and liver by immunohistochemistory and IL-10 producing Tregs by flowcytometry to clarify the role of IgG4 and Tregs in AIP. Subjects and Methods: The 6 AIP patients were obtained from Kansai Medical University. 6 cases of chronic pancreatitis were served as disease control. Hepatic tissue was sectioned from 16 IgG4-SC patients and 26 patients with PSC. All AIP and 14 IgG4-SC patients were diagnosed by Asian criteria. One IgG4-SC patient was diagnosed by Mayo (HISORt) criteria and other was diagnosed by biopsy. We studied infiltrating IgG4-positive cells and Tregs in the pancreas and liver by immunohistochemistry. IL-10 producing Tregs were analyzed from peripheral blood by flow cytometry. Results: In the pancreas, Tregs were increased in the pancreas with AIP (24.6±18.0 cells/HPF) compared with controls (5.1±4.3 cells/HPF). The numbers of IgG4positive plasma cells were significantly higher in AIP (18.6±10.3 cells/HPF) than in controls (1.1±0.7 cells/HPF). However, there were no significant differences in CD3+, CD4+, or CD79+ cells between the AIP (CD3: 63.1±27.1, CD4: 48.2±32.9, CD79: 24.1±9.2 cells/ HPF) and control sections (CD3: 73.6±37.1, CD4: 34.0±23.8, CD79: 14.5±14.6 cells/HPF). In the liver, the numbers of IgG4-positive plasma cells were significantly higher in IgG4SC (16.6±7.7 cells/HPF) than in PSC (4.0±0.7 cells/HPF). Tregs in the patients with IgG4SC (5.4±1.5 cells/HPF) were also significantly increased compared with PSC (2.0±0.3 cells/ HPF). In the patients with IgG4-SC, the numbers of infiltrated Tregs were significantly positively correlated with IgG4-positive plasma cells (R=0.75). In patients with the untreated AIP, IL-10 producing Tregs and IgG4 also positively correlated (R=0.53). Conclusion: In AIP, abundant infiltration of Tregs may affect the switching of B cells to IgG4-producing plasmacytes.

Background : Auto-immune pancreatitis (AIP) should be suspected in patients with unexplained pancreatitis. AIP is recognized according to HISORt criteria (including histology, pancreatic imaging, elevated serum IgG4 level and response to steroid therapy) as recently proposed by the Mayo Clinic. These criteria are highly selective and often difficult to fulfill. Previous studies suggested that carbonic anhydrase (CA) II is a target antigen in AIP. The aim of the present study was to evaluate the prevalence of serum antibodies to CA II in patients with AIP. Patients and Methods : 21 patients with AIP fulfilling HISORt criteria were retrospectively studied. An enzyme-linked immunosorbent assay was used to quantify serum antibodies to CA II. The concentrations of serum IgG4were measured by nephelemetry with a cut-off of 2 g/L. Thirty two patients with pancreatic adenocarcinoma or non-auto immune pancreatitis, and 96 healthy subjects served as controls. Results : 21 patients (13 males), median age 37 years [21-70] had AIP, histologically defined (57%) or with typical pancreatic imaging and response to steroids (43%). Pancreatic imaging revealed mass or irregular ducts in 71% and 48% of the cases, respectively. Four patients had ulcerative colitis. Serum IgG4 were elevated in 1 patient (5%). Serum antibodies to CA II were present in 2 patients (10%). Both had a pancreatic mass, and underwent pancreaticoduodenectomy. They developed post-operative, steroid-sensitive cholangitis. Serum antibodies to CA II were present in 3 healthy controls (3%) and in 1 subject with alcoholic chronic pancreatitis (3%). No patient with pancreatic cancer had serum antibodies to CA II. The sensitivity, specificity, positive and negative predictive values of antibodies to CA II for the diagnosis of AIP were 10%, 97%, 33%, et 87%, respectively. Conclusion : 10% of patients with well-defined AIP have serum antibodies to CA II in an European center. This prevalence is in accordance with previously reported studies, but lower than in Japanese series. The high specificity of CA II antibodies might be helpful for AIP diagnosis, particularly when serum IgG4 is normal.

nant negative MyD88 ,.',*as performed using respective adenovims vectors. RESULTS: The primary cultures ~creted large amounts of superoxide 1150 nmoVmg protein/ha, while the cell lines produced small amounts (2-3 nmoFmg pmteiru%) Among the Nox/Duox family, only Noxi iso[brm was expressed in the colonic epitheIiai cells tested Primary cultured ceils also expressed p22-phox, p67-phox, and racl, but cancer cell lines possessed p22phox and racl. Owrexpression of p67-phox failed to increase superoxide generation in Caco2 cells, but co-transtection of p67q)hox and p47-phox up-regulated the production 10.4bid None of cyiokines (IL-l-beta, TNF-alpha and [FN-gamma), grovah factors (EGF and TGF-beta), E. colt LPS, and PMA up-regulated the Noxl activity Salmondla [lagellin (FIIC) sumulated constitutively expressed TLR5 in Caco2 cells, phosphorylated TAKIFFA81, and increased superoxide production 2-{old Tins up-regulation was cancelled by dominant negative MyD88 DISCUSSION: Our results show that the cytosolic components (p67-phox ang4~r p47-phox) are required tnr full activation of the potent Noxl expressed in colonic epithelial cells Noxl expressed on surface mucous cells of the colon may play an important role in host epithelial cell-bacterial interactions for I:lost defmzse