Kazuya Yoshizawa

Serum Interleukin-6, Insulin, and HOMA-IR in Male Individuals with Colorectal Adenoma

Purpose: It is widely acknowledged that chronic low-grade inflammation plays a key role in the development of obesity-related insulin resistance and type 2 diabetes. The level of circulating interleukin-6 (IL-6), one of the major proinflammatory adipokines, is correlated with obesity and insulin resistance, which are known to be risk factors for colorectal adenoma. We examined the association between the circulating level of IL-6 and the presence of colorectal adenoma. Experimental Design: In a total colonoscopy-based cross-sectional study conducted between January and December 2008, serum levels of IL-6 were measured in samples of venous blood obtained from 336 male participants attending health checkups (118 individuals with colorectal adenoma and 218 age-matched controls) after an overnight fast. Results: In the colorectal adenoma group, the median levels of serum IL-6 (1.24 vs. 1.04 pg/mL; P = 0.01), triglyceride, insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) were to be significantly higher than those in the control group. When restricted to individuals with adenoma, levels of IL-6 were positively correlated with body mass index, insulin, and HOMA-IR. Multiple logistic analyses adjusted to include insulin or HOMA-IR showed that high levels of IL-6 were associated with the presence of colorectal adenoma. There was no significant interaction of IL-6 with HOMA-IR to modify this association. Conclusions: Our findings suggest that increased serum levels of IL-6 are positively associated with the presence of colorectal adenoma in men, independently of insulin and HOMA-IR. Clin Cancer Res; 18(2); 392–9. ©2011 AACR.

Production of Interleukin-10 by Combining a Granulocyte and Monocyte Adsorption Carrier With Ulinastatin

Interleukin (IL)‐10 is an anti‐inflammatory cytokine mainly produced by monocytes and is essential for the induction of anti‐inflammatory intestinal macrophages with macrophage colony‐stimulating factor (M‐CSF). Thus, IL‐10‐ and M‐CSF‐rich conditions in colonic tissues seem to contribute to the improvement of pathological conditions in patients with inflammatory bowel diseases (IBD). We have already reported that ulinastatin, a serine protease inhibitor, increases M‐CSF production during granulocyte/monocyte (GM) adsorption to cellulose acetate (CA) beads (carriers for Adacolumn therapy). However, the effects of ulinastatin on IL‐10 production have not been clarified. The aim of the present study was to clarify the effects of ulinastatin on IL‐10 production during GM adsorption by in vitro experiments. Peripheral blood was divided into four groups: (Control) no ulinastatin added, no contact with CA beads; (1) no ulinastatin added, contact with CA beads; (2) ulinastatin added, no contact with CA beads; and (3) ulinastatin added, contact with CA beads. After incubation, IL‐10 in the plasma was measured. Compared with the level in the Control group, plasma IL‐10 was significantly higher only in group 3, in which ulinastatin was added in the presence of CA beads, but did not increase in the absence of CA beads. These results suggest that ulinastatin synergistically increases IL‐10 production with monocyte adsorption stimuli. By increasing not only M‐CSF but also IL‐10, a combination of ulinastatin and Adacolumn therapy may improve clinical efficacy for the treatment of IBD in terms of the induction of anti‐inflammatory intestinal macrophages.

Effect of Cellulose Acetate Beads on Interleukin-23 Release

Interleukin (IL)‐23, which is released by activated monocytes and neutrophils, promotes production of high levels of IL‐17 by T‐helper 17 cells. Cellulose acetate (CA) beads are used as carriers for granulocyte and monocyte (GM) adsorptive apheresis using Adacolumn. Contact between blood and CA beads induces cytokine release; however, their inflammatory effects on IL‐23 release are unclear. We aimed to clarify the effect of CA beads on IL‐23 release in vitro. We incubated peripheral blood with and without CA beads and measured IL‐23. Compared to blood samples incubated without CA beads, blood samples incubated with CA beads had significantly decreased amounts of IL‐23. In conclusion, CA beads inhibited IL‐23 release from adsorbed GMs. The biological effects of this decrease in IL‐23 release during GM adsorption to CA beads need further clarification.

Esophageal carcinoid tumor treated by endoscopic resection.

The present report describes a rare case of esophageal carcinoid tumor that was treated by endoscopic resection. A 43‐year‐old woman underwent esophagogastroduodenoscopy at her family clinic for screening of the upper digestive tract and a small lesion resembling a submucosal tumor was detected in the lower esophagus. A biopsy sample from the lesion was diagnosed as esophageal carcinoid tumor and the patient visited our hospital for detailed examination. The tumor was approximately 3 mm in diameter and its surface appeared to be covered with normal squamous epithelium. The tumor had a shiny reddish surface without ulceration or erosion. Magnifying endoscopy with narrow‐band imaging showed structures resembling reticular vessels under the epithelium. Endoscopic ultrasonography depicted the tumor as a low‐echoic mass within the lamina propria. Computed tomography did not detect the tumor and no metastatic lesions were evident in other organs. With the patients informed consent, the tumor was resected using endoscopic submucosal dissection, with a sufficient free margin in both the vertical and horizontal directions. Magnifying endoscopic examination showed the resected tumor to have abundant reticular vessels. Finally, the tumor was diagnosed immunopathologically as an esophageal carcinoid tumor (neuroendocrine cell tumor, grade 1), without lymphatic or vascular invasion.

Relationship Between Tumor Necrosis Factor-α Release and Granulocyte and Monocyte Adsorption to Cellulose Acetate Beads

Tumor necrosis factor‐α, (TNF)‐α, a proinflammatory cytokine, is produced by activated granulocytes and monocytes (GMs) and implicated as a major factor in inflammatory bowel disease (IBD) pathogenesis. Reduction of TNF‐α should improve IBD pathology. GM adsorptive apheresis (GMA) is an effective therapy for inflammatory disorders including IBD. GM adsorption to cellulose acetate (CA) beads induces anti‐inflammatory cytokine release, although these effects on TNF‐α release are not clarified. We hypothesized that GMA may inhibit TNF‐α release. The aim of the present study was to clarify the effects of GM adsorption to CA beads on TNF‐α release in vitro. Peripheral blood was incubated with and without CA beads and TNF‐α was measured. For comparison, TNF‐α was measured in another lipopolysaccharide (LPS)‐containing peripheral blood sample incubated similarly. The amount of TNF‐α in blood samples incubated with CA beads was significantly higher than in those incubated without beads, although it was significantly lower than TNF‐α incubated with LPS‐containing sample without beads. The amount of TNF‐α after incubation with CA beads positively correlated with GM adsorption ratio. GM adsorption to CA beads induced a small amount of TNF‐α release. This is the first report on TNF‐α release induced via GM adsorption stimuli. The biological effects of TNF‐α release during GM adsorption need to be clarified.

Treatment with Anti-Interleukin-6 Receptor Antibody Ameliorates Intestinal Polyposis in Apc Min/+ Mice under High-Fat Diet Conditions

The prevalence of colorectal malignancies is increasing in the world. The parallel increase of metabolic syndrome gives a speculation between these two conditions, although the precise mechanism is still unclear. Interleukin-6 (IL-6) is a cytokine known to correlate with obesity and serve as a proinflammatory adipokine. In the present study, we investigated the effect of IL-6 signaling blockade on intestinal polyp formation in obesity using a mouse model of adenomatous polyposis coli (Apc). Male C57BL/6J-Apc(Min/+) mice were fed a high-fat diet from 5 weeks of age, and the overweight mice thus obtained were given a weekly intraperitoneal injection of anti-mouse IL-6 receptor antibody (MR16-1) from 6 to 15 weeks of age, while control mice received IgG or phosphate-buffered saline (PBS). The total number of intestinal polyps was significantly decreased in the MR16-1-injected group (53.1 ± 6.8) relative to the control groups (PBS-injected, 81.3 ± 6.1; rat IgG-injected, 74.7 ± 4.8, p = 0.01), and in particular the number of polyps larger than 2 mm in diameter was markedly decreased. In addition, the mean diameter of polyps in the MR16-1-injected group was significantly smaller than that in the control groups. On the other hand, no significant differences in body weight, epididymal fat pad mass, or the plasma levels of glucose, insulin and triglyceride were observed among the three groups. Thus, treatment with anti-IL-6 receptor antibody suppressed polyp growth in obese Apc(Min/+) mice fed the high-fat diet. We suggest that IL-6 signaling may be responsible for the obesity-associated colorectal tumorigenesis.

Increased Levels of Serum Glucose-Dependent Insulinotropic Polypeptide as a Novel Risk Factor for Human Colorectal Adenoma

Author contributions: Yu Sasaki: design an writing. Hiroaki Takeda: design and conduct and analysis, and data interpretation. Tomo Shoichi Nishise: data interpretation and man Tanaka: design and conduct of the study, and manuscript writing. ⁎ Corresponding author. Tel.: +81 23 628 5309 E-mail addresses: y-sasaki@med.id.yama stakeshi@med.id.yamagata-u.ac.jp (T. Sato), nagino@med.id.yamagata-u.ac.jp (K. Nagino ytanaka@tohoku-ctr-hsp.com (Y. Tanaka), y-

Characteristics of Small Bowel Polyps Detected in Cowden Syndrome by Capsule Endoscopy

Cowden syndrome is an uncommon, autosomal dominant disease characterized by multiple hamartomas and hyperplastic lesions in the skin, mucous membrane, brain, breast, thyroid, and gastrointestinal tract. About 30% of Cowden syndrome cases are reportedly complicated by malignant diseases. Hamartomatous polyps occur throughout the gastrointestinal tract, the most common sites being the stomach, colon, esophagus, and duodenum. Small bowel polyps can occur in Cowden syndrome; however, they are difficult to detect by conventional examination, including double-contrast X-ray study. Here, we report three cases of Cowden syndrome with small bowel polyps, which were detected by capsule endoscopy. The small bowel polyps of Cowden syndrome frequently occur at the oral end of the small bowel, especially in the duodenum and jejunum, and their color is similar to that of the surrounding mucosa; additionally, the polyps are relatively small (2–5 mm). Capsule endoscopy is useful for detecting small bowel polyps in Cowden syndrome.

Tu2130 Anti-Mouse IL-6 Receptor Antibody Suppresses Intestinal Carcinogenesis in APCMIN/+ Mice Receiving a High-Fat Diet

9, respectively) were cultured on the rat or human subcutaneous adipose tissue-embedded or -nonembedded gel. Adipose tissue promoted the expression of the growth markers, Ki67 antigen and 24 h-labeling bromodeoxyuridine (BrdU) in the cancer cell types, whereas it inhibited that of the apoptosis marker, cleaved caspase 3. Adipose tissue promoted the basal and superficial expression of the differentiation markers, p63 and involucrin, respectively, within the epithelial layer formed by cancer cell types. Adipose tissue accelerated the invasion of cancer cell types into the gel, together with increased expression of filamin A, laminin-5 and membrane type 1-matrix metalloproteinase (MT1-MMP), and with decreased display of E-cadherin. Adipose tissue promoted the expression of mitogen-activated protein kinase (MAPK: Raf-1, MEK-1 and pERK-1/2) and phosphoinositide 3-kinase-Akt (PI3K-Akt: PTEN, p-4E-BP1 and S6) pathways, and insulin-like growth factor-I receptor (IGF-IR) in the cell types, while it decreased that of the molecularly targeted protein, human epidermal growth factor receptor 2 (HER2). Adipose tissue did not affect the expression of the prostaglandin biosynthetic enzyme cyclooxgenase-2 (COX-2) in the cell types. The COX-2 inhibitor celecoxib did not affect the morphology and invasion of the cell types. Cancer cell types in turn decreased adiponection, leptin and registin production in adipose tissue. The data suggest, first, that adipose tissue may influence the progression of esophageal cancer with the increased growth/invasion and the decreased apoptosis through MAPK, PI3K-Akt and IGF-IR up-regulation in a COX-2-independent way, although adipose tissue seems to induce the differentiation of cancer cells; second, that adipose tissue may adversely affect the HER2targeted therapy; and third, that the cancer cells may affect adipokine production of adipose tissue. Collectively, we conclude that adipose tissue may be involved in the progression of esophageal cancer under adipose tissue-cancer cell interaction.