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Biomedical subjects

Akira Andoh

Publications and source records attributed to Akira Andoh.

At least 37 records · Page 2Linked to original sources
PubMed2005

Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts.

BACKGROUND & AIMS: Interleukin (IL)-22, a member of the IL-10 subfamily, is a recently identified T-cell-derived cytokine. We investigated IL-22 expression in the inflamed mucosa of patients with inflammatory bowel disease (IBD) and analyzed its biologic activities in human colonic subepithelial myofibroblasts (SEMFs). METHODS: Mucosal IL-22 expression was evaluated by immunohistochemical procedures. The effects of IL-22 on colonic SEMFs were investigated by cDNA microarrays, Northern blots, enzyme-linked immunosorbent assay, and electrophoretic gel mobility shift assays (EMSAs). RESULTS: IL-22 was not detectable in normal colonic mucosa. In IBD mucosa, IL-22 expression was detectable in CD4-positive T cells. IL-22-positive cells were increased in ulcerative colitis and even more so in Crohn's disease. IL-22 receptor expression colocalized with a marker of SEMFs. IL-22 did not modulate SEMF proliferation and collagen synthesis. cDNA microarray analyses demonstrated that, in colonic SEMFs, IL-22 increased the messenger RNA (mRNA) expression of inflammatory cytokines (IL-6, IL-8, IL-11, and leukemia inhibitory factor [LIF]), chemokines, and matrix metalloproteinases. IL-22 induced an activation of nuclear factor (NF)-kappaB and activating protein (AP)-1 within 1 hour, and a blockade of NF-kappaB and AP-1 activation markedly reduced IL-22 induction of IL-6, IL-8, IL-11, and LIF mRNA. MAP-kinase inhibitors (PD98059, U0216, and SB202190) significantly reduced IL-22 induction of cytokine secretion. The combination of either IL-17 plus IL-22 or IL-19 plus IL-22 additively up-regulated cytokine secretion. CONCLUSIONS: IL-22 derived from activated T cells acts on SEMFs to elicit expression of proinflammatory cytokines and matrix-degrading molecules indicating proinflammatory/remodeling roles in IBD.

Colon↗
PubMed2005

Interleukin-17 and lipopolysaccharides synergistically induce cyclooxygenase-2 expression in human intestinal myofibroblasts.

BACKGROUND: Colonic subepithelial myofibroblasts (SEMF) play a role in the modulation of mucosal inflammatory responses via the secretion of various inflammatory mediators. In the present study the effects of interleukin (IL)-17 and lipopolysaccharides (LPS) on cyclooxygenase (COX) expression in colonic SEMF were investigated. METHODS: The expression of COX-1 and -2 proteins and mRNAs were determined by western and northern blotting, respectively. Nuclear factor (NF)-kappaB DNA binding activities were evaluated by electrophoretic gel mobility shift assays (EMSA). RESULTS: The expression of COX-2 protein and mRNA was rapidly induced by the addition of IL-17 and LPS, whereas COX-1 expression was not affected by these factors. The effects of IL-17 and LPS were detected in a dose- and time-dependent manner. Furthermore, IL-17 and LPS synergistically induced COX-2 mRNA and protein expression. The EMSA demonstrated that the addition of IL-17 and LPS induced NF-kappaB activation within 1.5 h after stimulation, and a blockade of NF-kappaB activation by a recombinant adenovirus containing a stable form of IkappaBa markedly reduced the IL-17- and LPS-induced COX-2 mRNA expression. In these cells, the expression of Toll-like receptor (TLR)-4, which is a cellular receptor for LPS, was detected. CONCLUSION: Interleukin-17 and LPS play an important role in the induction of COX-2 in SEMF. These findings suggest that COX-2 expression and prostaglandin synthesis might be regulated by both T-cell-derived factor (IL-17) and bacterial products (LPS) in the inflamed mucosa.

Blotting, Northern↗
PubMed2005

Elevated circulating platelet-derived microparticles in patients with active inflammatory bowel disease.

OBJECTIVES: Platelet-derived microparticles (PDMPs) are active molecules involved in the hemostatic and inflammatory responses. To evaluate the changes in the platelet function in patients with inflammatory bowel disease (IBD), we measured circulating PDMP levels. METHODS: Twenty-five healthy controls, 44 patients with ulcerative colitis (UC), and 43 patients with Crohn's Disease (CD) were studied. The PDMP and soluble P-selectin (sP-selectin) levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: In the healthy controls, the PDMP levels were 17.2 +/- 6.2 U/mL. Significant differences were not observed between the healthy controls and inactive UC patients (20.8 +/- 9.5 U/mL, n = 25) or between the healthy controls and inactive CD patients (17.6 +/- 7.8 U/mL, n = 24). In contrast, the PDMP levels were significantly higher in both active UC (49.2 +/- 33.6 U/mL, n = 19) and active CD (48.6 +/- 42.8 U/mL, n = 19) patients than in the healthy controls. A significant correlation was found between the PDMP levels and the clinical activity indexes (CAI) of UC patients (r = 0.65, p < 0.01, n = 44), and between the PDMP levels and Crohn's disease activity indexes (CDAI) (r = 0.72, p < 0.01, n = 43). Elevated PDMP levels in active patients were significantly reduced after remission. A significant correlation was observed between the PDMP levels and the sP-selectin levels (r = 0.60, p < 0.01, n = 122). CONCLUSION: Elevated circulating PDMPs in active IBD patients suggest a role for platelets in the pathogenesis of IBD.

Acute Disease↗
PubMed2005

A case of severe acute pancreatitis treated with CTR-001 direct hemoperfusion for cytokine apheresis.

Severe acute pancreatitis is a clinical entity that can develop into multiple organ failure (MOF), and still has a poor prognosis. It is generally agreed that excessive humoral mediators such as pro-inflammatory cytokines play important roles in the pathogenesis of organ failure in patients with severe acute pancreatitis (SAP). Furthermore, it has been reported that continuous hemodiafiltration (CHDF) can remove the excess humoral mediators during the hypercytokinemic state of systemic inflammatory response syndrome (SIRS). We experienced a case of severe acute pancreatitis induced by alcohol abuse, on whom we performed cytokine apheresis. The patient was a 46 year-old male. He received 14 cytokine apheresis procedures, for about 4 hours in each session, using a CTR-001 direct hemoperfusion (DHP) cartridge. His serum levels of pro-inflammatory cytokines such as interleukin-6 (IL-6; 1649.1+/-667.1-1257.1+/-489.4 pg/mL, P=0.013) decreased significantly after the CTR-001 procedures. However tumor necrosis factor-alpha (TNF-alpha) (26.2+/-1.7-24.3+/-1.9 pg/mL, P=0.087), IL-1beta (6.1+/-2.9-3.49+/-1.1 pg/mL, P=0.477), IL-8 (192.5+/-33.4-229.5+/-51.8 pg/mL, P=0.754) and IL-10 (14.4+/-2.7-14.0+/-1.9 pg/mL, P=0.726) did not decrease statistically. Therefore, we conclude that in this case, cytokine apheresis using a CTR-001 cartridge was effective for reducing the pro-inflammatory cytokines during severe acute pancreatitis.

Acute Disease↗
PubMed2005

Suppression of inflammatory cytokine secretion by granulocyte/monocyte adsorptive apheresis in active ulcerative colitis.

To elucidate the molecular mechanisms involved in the therapeutic effects of granulocyte/monocyte adsorption apheresis, changes were investigated in the cytokine responses of peripheral blood mononuclear cells (PBMC) before and after granulocyte/monocyte adsorptive apheresis in ulcerative colitis (UC) patients. Four patients with active UC were enrolled. All patients responded to granulocyte/monocyte adsorptive apheresis. A total of 20 sessions of four patients were analyzed. Peripheral blood mononuclear cells were isolated from peripheral venous blood within 5 min before and after each session of granulocyte/monocyte adsorptive apheresis. The cells were stimulated with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha for 24 h, and the secreted IL-8 and IL-6 levels were determined by enzyme-linked immunosorbent assay (ELISA). IL-1beta-induced IL-8 and IL-6 secretion was significantly decreased after granulocyte/monocyte adsorptive apheresis. TNF-alpha-induced IL-8 secretion was also significantly decreased after apheresis, but there was no significant difference in TNF-alpha-induced IL-6 secretion (P = 0.052). In conclusion, granulocyte/monocyte adsorptive apheresis down-regulates the IL-1beta- and TNF-alpha-induced inflammatory responses in PBMC. The induction of hyporesponsiveness to pro-inflammatory cytokines may be an important factor mediating the clinical effects of granulocyte/macrophage adsorptive apheresis in UC patients.

Adult↗
PubMed2005

Leukocytapheresis therapy modulates circulating t cell subsets in patients with ulcerative colitis.

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of leukocytapheresis (LCAP). We investigated the alterations in circulating T cell subsets after LCAP therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled. Fourteen patients were responders, and four patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after LCAP therapy. Flow cytometric analysis for T cell markers and intracellular interferon (IFN)-gamma (Th1) and interleukin (IL)-4 (Th2) was then performed. The average numbers of lymphocytes, T and B cells were significantly decreased after LCAP therapy, respectively (P < 0.01). The numbers of CD4+ and CD8+ T cells were also significantly decreased, respectively (P < 0.01), but the CD4+/CD8+ ratio was not changed. The number of CD45RO+ CD4+ memory T cells was significantly decreased. The number of CD25+ CD4+ T cells tended to decrease after LCAP therapy (not significant). However, the ratio of CD25+ CD4+-cells/CD25- CD4+-cells was significantly increased (P < 0.05). The number of IFN-gamma-positive (Th1) cells was significantly decreased after LCAP therapy, but there was no significant change in the number of IL-4-positive (Th2) cells. The Th1/Th2 ratio was significantly decreased after LCAP therapy. Some of the immuno-suppressive effects of LCAP therapy may be associated with a modulation of circulating T cell subsets.

Adult↗
PubMed2005

A yeast extract high in bioactive peptides has a blood-pressure lowering effect in hypertensive model.

It was reported that angiotensin-converting enzyme (ACE) plays an important role in increasing blood pressure. Recently, it was reported that several food hydrolysates have ACE inhibitory effects in the spontaneous hypertensive rat (SHR) model and mildly hypertensive subjects. Therefore, the anti-hypertensive effects of brewer's yeast BY-G were investigated, which contains many kinds of beneficial nutrients (vitamins, minerals, nucleic acids, glutathione, amino acids, etc.). The aim of this study was to evaluate the anti-hypertensive effects of BY-G and its component peptides obtained by enzymatic treatment. The peptide fraction KRF814 was obtained by the hydrolysate of BY-G with alkaline protease and then treated with Amberlite XAD-2. The KRF814, which has an inhibitory effect on ACE in vitro, was obtained. BY-G and KRF814 were fed to male SHR and showed significantly anti-hypertensive effects. KRF814 contained alanyl-phenylalanine (AF) and glycyl-phenylalanine (GF), which significantly decreased systolic BP in the SHR model. The active ingredients of KRF814, AF, and GF had about 60% of the potency of the positive control, which was captopril. It is considered that intake of BY-G or its component peptides as a functional food stuff might be beneficial for improving BP in people with hypertension.

Animals↗
PubMed2005

Interleukin-1beta and tumor necrosis factor-alpha upregulate interleukin-23 subunit p19 gene expression in human colonic subepithelial myofibroblasts.

The recently identified cytokine interleukin-23 (IL-23) consists of p19 and p40 subunits. The major cellular source of IL-23 is dendritic cells and/or macrophages. We investigated the expression of IL-23 p19 mRNA in human colonic subepithelial myofibroblasts (SEMFs). p19 mRNA was not expressed in unstimulated SEMFs, but IL-1beta and TNF-alpha strongly induced p19 mRNA expression in these cells. The effects of IL-1beta were much stronger than those of TNF-alpha. These responses were observed in both a dose- and time-dependent manner. Furthermore, these cytokines acted synergistically when used in combination. A blockade of NF-kappaB activation by the overexpression of a stable form of IkappaBalpha completely blocked these responses, indicating that the induction of p19 mRNA expression by IL-1beta and TNF-alpha was mediated by the NF-kappaB activation pathway. In conclusion, this is the first report demonstrating that IL-23 p19 mRNA is inducible in colonic myofibroblasts by IL-1beta and TNF-alpha. The p19 expression in these cells might play a role in mucosal immune responses.

Cells, Cultured↗
PubMed2005

[Cytoapheresis for IBD].

Ulcerative colitis (UC) is associated with chronic relapsing inflammation of the colon. Cytoapheresis is a therapeutic strategy of extracorporeal immunomodulation that has been used in several immunological disorders. In Japan, several open trials of cytoapheresis for UC patients accumulated encouraging results in bringing steroid-resistant patients into remission. In this paper, three types of cytoapheresis [leukocytapheresis (LCAP), granulocytapheresis (GCAP), and centrifugal leukocyte apheresis] are reviewed.

CD4-Positive T-Lymphocytes↗
PubMed2005

Development of dextran sulfate sodium-induced colitis is aggravated in mice genetically deficient for complement C5.

The complement system is a potent effector of innate immunity. To elucidate the pathophysiological role of the complement system in inflammatory bowel disease (IBD), we evaluated the development of dextran sulfate sodium (DSS)-induced colitis in genetically complement C5-deficient mice. We used DBA2/J mice, which are genetically deficient in complement C5. DBA1/J mice have a normal complement system, and were used as controls. Experimental colitis was induced by the oral administration of 3.5% (w/v) DSS in their drinking water for 10 days. On day 10, all mice were sacrificed and their colons were collected. The development of colitis was assessed by the histological score, disease activity index, myeloperoxidase (MPO) activity, and macroscopic changes of the colon. Body weight loss was more apparent in the DBA2/J mice than in control DBA1/J mice. The colon length was shorter in the DBA2/J mice than in DBA1/J mice. The disease activity index, histological colitis score, and MPO activity were all significantly higher in the DBA2/J mice than in DBA1/J mice. Microscopically, mucosal edema, cellular infiltration and disruption of the epithelium were much more severe in the DBA2/J mice than in DBA1/J mice. The development of DSS colitis was aggravated in genetically C5-deficient DBA2/J mice. These findings suggest that the complement system might play a protective role in the development of DSS-induced experimental colitis.

Animals↗
PubMed2004

Role of fibroblast growth factor-2 in the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in human intestinal myofibroblasts.

BACKGROUND AND AIMS: The coordinated expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) plays a crucial role in tissue remodeling. We investigated the effects of fibroblast growth factor (FGF)-2 on the secretion of MMPs and TIMPs in human intestinal subepithelial myofibroblasts (SEMFs). METHODS: The secretion of MMP-s and TIMPs was determined by ELISA or Western blotting. The mRNA expression of MMPs and TIMPs was assessed by Northern blotting. The activating protein (AP)-1-DNA binding activity was evaluated by electrophoretic gel mobility shift assays (EMSA). RESULTS: Unstimulated intestinal SEMFs constitutively secreted MMP-2 and TIMP-2. FGF-2 stimulated MMP-1, MMP-3 and TIMP-1 secretion, but did not affect MMP-2 or TIMP-2 secretion. FGF-2 induced AP-1-DNA binding activity, and the c-Jun/AP-1 inhibitor curcumin attenuated the FGF-2-induced MMP-1, -3 and TIMP-1 mRNA expression. Mitogen-activated protein (MAP) kinase inhibitors (U0126 and PD098059) also blocked the MMP-1, -3 and TIMP-1 secretion. Furthermore, FGF-2 dose-dependently induced FGF-2 mRNA expression in these cells. CONCLUSIONS: FGF-2 may be one of important regulatory factors for extracellular matrix turnover via a modulation of MMP and TIMP secretion from SEMFs.

Blotting, Western↗
PubMed2004

Inflixmab as a possible treatment for the hemorrhagic type of Crohn's disease.

Acute lower gastrointestinal bleeding is a rare complication of Crohn's disease (CD). Although anti-tumor necrosis factor-alpha (TNF-alpha, infliximab) therapy has been established for patients with inflammatory and fistulous CD, there has been little evidence on whether infliximab is effective for the hemorrhagic type of CD. We report a case of a 31-year-old man with CD who had recurrent sudden-onset bloody stool. After a second surgery, he visited our hospital because of bloody stool. Infusion of infliximab stopped the bleeding and promoted the healing of ulcers in the ileum and ileocolon anastomosis. We suggest that infliximab therapy should be tried to stop acute gastrointestinal bleeding in CD before there is a surgical emergency.

Adult↗
PubMed2004

Suppression of interleukin-1beta- and tumor necrosis factor-alpha-induced inflammatory responses by leukocytapheresis therapy in patients with ulcerative colitis.

BACKGROUND: To elucidate the molecular mechanisms involved in the therapeutic effects of leukocytapheresis (LCAP), we investigated the alterations in the cytokine responses of peripheral blood mononuclear cells (PBMCs) before and after LCAP therapy in ulcerative colitis (UC) patients. METHODS: Twelve patients with UC who did not respond to steroid therapy were enrolled. Nine patients responded to LCAP therapy, but 3 patients did not show clinical improvement. PBMCs were isolated from peripheral venous blood obtained within 5 min before and after the first and second session of LCAP treatment. Cells were stimulated with interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha for 24 h, and the levels of secreted IL-8 and IL-6 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: LCAP induced a significant decrease in peripheral lymphocyte, monocyte, and platelet counts. IL-1beta- and TNF-alpha-induced IL-8 and IL-6 secretion was significantly decreased after the first and second LCAP treatments. These responses were associated with inhibitory effects on nuclear factor (NF)-kappaB DNA-binding activity. CONCLUSIONS: LCAP downregulates the IL-1beta- and TNF-alpha-induced inflammatory responses in PBMCs isolated from UC patients. The induction of hyporesponsiveness to proinflammatory cytokines may be an important factor mediating the clinical effects of LCAP in UC patients.

Adult↗
PubMed2004

Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice.

We evaluated the effects of rat anti-mouse IL-17 neutralizing monoclonal antibody (mAb) on the development of dextran sulfate sodium (DSS)-induced colitis. Tissue samples were evaluated by standard immunohistochemical procedure. The mucosal mRNA expression of cytokines was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). In the mice treated with the anti-IL-17 mAb, the body weight was significantly lower, and anal prolapse and colon shortening were apparent. A histological analysis indicated that the anti-IL-17 mAb markedly enhanced the severity of colitis. The mucosal infiltration of CD4-positive helper T cells and CD11b-positive granulocytes-monocytes was increased in the anti-IL-17 mAb-treated mice. Treatment with the anti-IL-17 mAb increased the mucosal expression of mRNAs of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, IL-6, RANTES, and IP-10. Blocking of IL-17 activity in vivo using the anti-IL-17 mAb enhanced the development of DSS-colitis in mice. This suggests an inhibitory role for IL-17 in the development of DSS-colitis.

Animals↗
PubMed2004

A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.

BACKGROUND & AIMS: Interleukin-6 (IL-6) regulates immune response and inflammation. We carried out a pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA, a humanized monoclonal antibody to IL-6 receptor, in patients with active Crohn's disease. METHODS: Thirty-six patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =150) were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. The study's primary end point was a clinical response rate that was defined as a reduction of CDAI > or =70. RESULTS: At the final evaluation, 80% of the patients (8 of 10) given biweekly MRA had a clinical response as compared with 31% of the placebo-treated patients (4 of 13; P = 0.019). Twenty percent of the patients (2 of 10) on this regimen went into remission (CDAI <150), as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every-4-week regimen was 42% (5 of 12). The serum concentrations of MRA were detected at 2 weeks after every infusion, at which time acute phase responses were completely suppressed; however, they were not suppressed at 4 weeks. Endoscopic and histologic examination showed no difference between MRA and placebo groups. The incidence of adverse events was similar in all the groups. CONCLUSIONS: This is the first clinical trial of humanized anti-IL-6 receptor monoclonal antibody in Crohn's disease. A biweekly 8 mg/kg infusion of MRA was well tolerated, normalized the acute-phase responses, and suggests a clinical effect in active Crohn's disease.

Adult↗
PubMed2004

Fibroblast growth factor-2 stimulates interleukin-6 secretion in human pancreatic periacinar myofibroblasts.

OBJECTIVES: Fibroblast growth factor-2 (FGF-2) plays an important role in the pathophysiology of acute and chronic pancreatitis. In the present study, to evaluate the proinflammatory nature of FGF-2, we investigated the effects of FGF-2 on IL-6 secretion in human pancreatic periacinar myofibroblasts. METHODS: IL-6 supernatant levels were determined by enzyme-linked immunosorbent assays (ELISA). IL-6 mRNA expression were determined by Northern blots and quantitative PCRs. Activated protein (AP)-1 DNA-binding activities were evaluated by electrophoretic gel mobility shift assays (EMSA). RESULTS: FGF-2 induced IL-6 release in a dose- and time-dependent manner. FGF-2 activity for IL-6 induction was the same as that of IL-17. The combination of FGF-2 and IL-17 exerted additive effects at mRNA and protein levels. FGF-2 induced AP-1 DNA-binding activity, but blockage of AP-1 signaling by adenovirus-mediated transfer of a dominant negative c-Jun gene did not affect FGF-2-induced IL-6 mRNA expression. FGF-2 rapidly induced activation of ERK1/2 and p38 MAP kinases, and specific inhibitors for these enzymes significantly reduced FGF-2-induced IL-6 release. CONCLUSION: In the pancreas, FGF-2 may not only play a role as a growth factor in tissue injury repair processes but also as an inducer of acute-phase response via stimulation of IL-6 release.

Adenoviridae↗
PubMed2004

Immunohistochemical analysis of short-segment Barrett's esophagus.

BACKGROUND AND AIMS: The majority of dysplasias and adenocarcinomas in Barrett's esophagus are closely associated with the specialized columnar epithelium. In this study, we performed an immunohistochemical analysis of columnar metaplasia presenting in short-segment Barrett's esophagus (SSBE). PATIENTS AND METHODS: The endoscopic biopsy specimens obtained from 91 patients were analyzed. Ten were cases of long-segment Barrett's esophagus (LSBE) and 81 had SSBE. Expression of MUC2, MUC5AC, Con A and CD10 was evaluated using immunohistochemical staining. RESULTS: All samples from LSBE (n = 9) were histologically diagnosed as specialized columnar epithelium. The 81 SSBE samples were divided into gastric fundic-type (n = 26), junctional-type (n = 16) and specialized columnar epithelium (n = 39). In the specialized columnar epithelium of SSBE, there was a predominance of goblet cell-type metaplasia proposed by Watanabe et al. which is characterized by MUC2-positive pyloric epithelium (66.7%). The total percentage of non-goblet cell-type and goblet cell-type was 76.9%. In contrast, 80% of LSBE revealed the large intestinal-type or the large and small intestinal-type. The long oval and villous pit by magnifying endoscope suggests the presence of the specialized columnar epithelium, but the phenotypic classification of Watanabe's criteria was not associated with the endoscopic pit pattern. CONCLUSION: Intestinal metaplasia in Barrett's esophagus changes immunohistochemically with progress of the disease.

Barrett Esophagus↗