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| 1.
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Sakamoto, Aiji ; Sugamoto, Yuka ; Tokunaga, Y. ; Yoshimuta, Tsuyoshi ; Hayashi, Kenshi ; Konno, Tetsuo ; Kawashiri, Masa-aki ; Takeda, Yoshiyu ; Yamagishi, Masakazu ; 林, 研至 ; 今野, 哲雄 ; 川尻, 剛照 ; 武田, 仁勇 ; 山岸, 正和
概要:
金沢大学医薬保健研究域医学系<br />Ephrin B1 and its cognate receptor, Eph receptor B2, key regulators of embryogenesis, are expressed
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in human atherosclerotic plaque and inhibit adult human monocyte chemotaxis. Few data exist, however, regarding the gene expression profiles of the ephrin (EFN) and Eph receptor (EPH) family of genes in atherosclerosis-related human cells. Gene expression profiles were determined of all 21 members of this gene family in atherosclerosis-related cells by reverse transcription-polymerase chain reaction analysis. The following 17 members were detected in adult human peripheral blood monocytes: EFNA1 and EFNA3 - EFNA5 (coding for ephrins A1 and A3 - A5); EPHA1, EPHA2, EPHA4 - EPHA6 and EPHA8 (coding for Eph receptors A1, A2, A4 - A6 and A8); EFNB1 and EFNB2 (coding for ephrins B1 and B2); and EPHB1 - EPHB4 and EPHB6 (coding for Eph receptors B1 - B4 and B6). THP-1 monocytic cells, Jurkat T cells and adult arterial endothelial cells also expressed multiple EFN and EPH genes. These results indicate that a wide variety of ephrins and Eph receptors might affect monocyte chemotaxis, contributing to the development of atherosclerosis. Their pathological significance requires further study. © 2011 Field House Publishing LLP.
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| 2.
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Xu, Liang ; Nagata, Naoto ; Nagashimada, Mayumi ; Zhuge, Fen ; Ni, Yinhua ; Chen, Guanliang ; Mayoux, Eric ; Kaneko, Shuichi ; Ota, Tsuguhito ; 長田, 直人 ; 金子, 周一 ; 太田, 嗣人
概要:
金沢大学医薬保健研究域医学系<br />Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading t
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o blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with empagliflozin for 16 weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver.
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| 3.
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Xu, Liang ; Nagata, Naoto ; Nagashimada, Mayumi ; Zhuge, Fen ; Ni, Yinhua ; Chen, Guanliang ; Kamei, Junzo ; Ishikawa, Hiroki ; Komatsu, Yasuhiko ; Kaneko, Shuichi ; Ota, Tsuguhito ; 長田, 直人 ; 金子, 周一 ; 太田, 嗣人
概要:
金沢大学医薬保健研究域医学系<br />Nonalcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver. NAFLD i
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s associated with hepatic inflammation and oxidative stress, resulting in nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Placental extracts have been used to treat various chronic diseases due to their antioxidative effect. However, the effects of the extracts on the development of NASH have yet to be elucidated. Here, we demonstrated that supplementation with an oral porcine placental extract (PPE) attenuated lipid accumulation and peroxidation, insulin resistance, inflammatory and stress signaling, and fibrogenesis in the liver of NASH model mice fed a high-cholesterol and high-fat diet. The PPE reduced the number of M1-like liver macrophages, but increased the number of anti-inflammatory M2-like macrophages, resulting in a predominance of M2 over M1 macrophage populations in the liver of NASH mice. Accordingly, the PPE suppressed lipopolysaccharide-induced M1 polarization in isolated murine peritoneal macrophages, whereas it facilitated interleukin 4-induced M2 polarization. Furthermore, the PPE reduced the hepatic stellate cell (HSC) activation associated with the attenuated transforming growth factor-β/Smad3 signaling, both in the liver of NASH mice and in RI-T cells, a HSC line. The PPE may be a potential approach to prevent NASH by limiting lipid peroxidation, promoting M2 macrophage polarization, and attenuating HSC activation. © Xu et al.
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| 4.
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Urai, Tamae ; Nakajima, Yukari ; Mukai, Kanae ; Asano, Kimi ; Okuwa, Mayumi ; Sugama, Junko ; Nakatani, Toshio ; 中島, 由加里 ; 向井, 加奈恵 ; 大桑, 麻由美 ; 須釜, 淳子 ; 中谷, 壽男
概要:
金沢大学医薬保健研究域<br />It was unclear that wound healing was delayed in obesity without hyperglycemia. The purpose of this stu
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dy was to compare the wound healing process between obese and non-obese mice without hyperglycemia by attaching a splint. Three-week-old male mice (C57BL/6N) were fed high-fat diets (60% of calories from fat) in the obesity group, and commercial diets in the control group for 15 weeks. Two circular (4 mm in diameter) full-thickness wounds were made on the dorsal skin. Body weights and serum leptin levels were significantly higher in the obesity group than in the control group until day 15 after wounding. Fasting blood glucose levels before wounding were lower in the obesity group than in a hyperglycemic rodent model. The macrophage infiltration into subcutaneous fat before wounding in the obesity group was negligible. The ratios of the wound area were not significantly different between the two groups. No significant differences were observed in the number of neutrophils or macrophages or new blood vessels and ratio of myofibroblasts or collagen fibers between the two groups. Our results demonstrated that cutaneous wound healing was not delayed in the obesity group without hyperglycemia and macrophage infiltration into the subcutaneous fat and with high serum leptin levels.
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| 5.
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Kitajima, Shunsuke ; Takahashi, Chiaki ; 北嶋, 俊輔 ; 髙橋, 智聡
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金沢大学がん進展制御研究所<br />The Retinoblastoma (RB) tumor suppressor regulates G1/S transition during cell cycle progression by m
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odulating the activity of E2F transcription factors. The RB pathway plays a central role in the suppression of most cancers, and RB mutation was initially discovered by virtue of its role in tumor initiation. However, as cancer genome sequencing has evolved to profile more advanced and treatment-resistant cancers, it has become increasingly clear that, in the majority of cancers, somatic RB inactivation occurs during tumor progression. Furthermore, despite the presence of deregulation of cell cycle control due to an INK4A deletion, additional CCND amplification and/or other mutations in the RB pathway, mutation or deletion of the RB gene is often observed during cancer progression. Of note, RB inactivation during cancer progression not only facilitates G1/S transition but also enhances some characteristics of malignancy, including altered drug sensitivity and a return to the undifferentiated state. Recently, we reported that RB inactivation enhances pro-inflammatory signaling through stimulation of the interleukin-6/STAT3 pathway, which directly promotes various malignant features of cancer cells. In this review, we highlight the consequences of RB inactivation during cancer progression, and discuss the biological and pathological significance of the interaction between RB and pro-inflammatory signaling. © 2017 Japanese Cancer Association.
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| 6.
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Koriyama, Yoshiki ; Nakayama, Yuya ; Matsugo, Seiichi ; Sugitani, Kayo ; Ogai, Kazuhiro ; Takadera, Tsuneo ; Kato, Satoru
概要:
Activated microglial cells play an important role in immune and inflammatory responses in CNS and play a role in neurode
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generative diseases. We examined the effects of lipoic acid (LA) on inflammatory responses of BV-2 microglial cells activated by lipopolysaccharide (LPS), and explored the underlying mechanisms of action of LA. BV-2 cells treated with LPS showed an up-regulation of mRNA of the pro-inflammatory molecules, inducible nitric oxide synthase (iNOS). LA suppressed the expression of iNOS and furthermore, LPS-induced production of nitrite. Moreover, LA suppressed the nuclear translocation of RelA, a component of nuclear factor-kappa B (NF-κB) that contains transcriptional activator domain for LPS. The mechanisms of LA-mediated anti-inflammatory effects on microglia remain unknown, and we suggested an involvement of Akt/glycogen synthase kinase-3β (GSK-3β) phosphorylation. The results showed that inhibitor of phosphatidylinositol 3-kinase prevented LA-mediated suppression of LPS induction of RelA and expression of iNOS. Furthermore, these inflammatory actions were prevented by GSK-3β inhibitors. These data demonstrate a role for LA as a chemical modulator of inflammatory responses by microglia, and thus may be a therapeutic strategy for treating neurodegenerative diseases with an inflammatory component. © 2013 Elsevier Ireland Ltd and the Japan Neuroscience Society.
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| 7.
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谷内江, 昭宏
概要:
金沢大学医薬保健研究域医学系<br />ヘムオキシゲナーゼ（heme oxygenase ; HO）はヘム代謝に関わる酵素であると同時に，細胞を酸化ストレスによる傷害から守る細胞保護蛋白である．HOの内，誘導酵素であるHO-1を欠損する症例
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の病態解析により，このようなHOの働きが特定の細胞の保護にとどまらず，多様な組織や臓器における細胞保護に関与していることが示された．また，腎組織や腎由来細胞株を用いた検討では，HO-1蛋白が特定の細胞に局在していること，それらの細胞ではHO-1産生が特に重要な意味を持つことが示唆された．さらに末梢血単球を用いた解析では，特定の単球亜群で恒常的にHO-1蛋白が発現していること，これらの単球が急性炎症疾患で増加することが示され，単球/マクロファージによるHO-1産生が炎症制御に重要な役割を果たすことが明らかとされた．一方で，HO-1遺伝子導入により過剰にHO-1蛋白を発現させた場合には，むしろ細胞傷害を促進する可能性があることも示され，生体内ではHO-1産生の局在や量が巧妙に制御されていることが示唆された．最近の報告では，HO-1蛋白が制御性T細胞による免疫制御に深く関わっている可能性も示されており，HO-1産生の誘導を標的とした介入が多様な炎症性疾患に対する新たな治療戦略の一つとして期待される． Heme oxygenase (HO) plays a central role in heme metabolism. At the same time, it protects cells from injury evoked by various oxidative stresses. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs. It is particularly important that in vivo HO-1 production is localized to selected cell types, e.g. renal tubular epithelium, reflecting the fact that HO-1 plays particularly important protective roles in these cells. In addition to renal epithelial cells and tissue macrophages, a minor subpopulation of circulating monocytes produced low, but significant levels of HO-1 and the number of these monocytes increased during episodes of acute inflammatory illnesses, indicating that monocytes play significant roles in controlling inflammation. On the other hand, excessive level of HO-1 induced by HO-1 gene transfection led to paradoxical susceptibility of the cells to oxidative injury. These results indicated that HO-1 expression is carefully controlled in vivo with regard to its location and the magnitude. Furthermore, it has been recently shown that HO-1 is involved in the immune regulation mediated by regulatory T cells. From these findings, it seems feasible to meticulously induce HO-1 protein in vivo as a novel therapeutic intervention to control various forms of inflammatory disorders.
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| 8.
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Motoo, Yoshiharu ; Shimasaki, Takeo ; Ishigaki, Yasuhito ; Nakajima, Hideo ; Kawakami, Kazuyuki ; Minamoto, Toshinari
概要:
金沢大学医薬保健研究域医学系<br />Pancreatic cancer develops and progresses through complex, cumulative biological processes involving
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metabolic disorder, local inflammation, and deregulated molecular pathways. The resulting tumor aggressiveness hampers surgical intervention and renders pancreatic cancer resistant to standard chemotherapy and radiation therapy. Based on these pathologic properties, several therapeutic strategies are being developed to reverse refractory pancreatic cancer. Here, we outline molecular targeting therapies, which are primarily directed against growth factor receptor-type tyrosine kinases deregulated in tumors, but have failed to improve the survival of pancreatic cancer patients. Glycogen synthase kinase-3β (GSK3β) is a member of a serine/threonine protein kinase family that plays a critical role in various cellular pathways. GSK3β has also emerged as a mediator of pathological states, including glucose intolerance, inflammation, and various cancers (e.g., pancreatic cancer). We review recent studies that demonstrate the anti-tumor effects of GSK3β inhibition alone or in combination with chemotherapy and radiation. GSK3β inhibition may exert indirect anti-tumor actions in pancreatic cancer by modulating metabolic disorder and inflammation. © 2011 by the authors; licensee MDPI, Basel, Switzerland.
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| 9.
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谷内江, 昭宏
概要:
ヘムオキシゲナーゼ（heme oxygenase ; HO）はヘム代謝に関わる酵素であると同時に，細胞を酸化ストレスによる傷害から守る細胞保護蛋白である．HOの内，誘導酵素であるHO-1を欠損する症例の病態解析により，このようなHOの働きが
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特定の細胞の保護にとどまらず，多様な組織や臓器における細胞保護に関与していることが示された．また，腎組織や腎由来細胞株を用いた検討では，HO-1蛋白が特定の細胞に局在していること，それらの細胞ではHO-1産生が特に重要な意味を持つことが示唆された．さらに末梢血単球を用いた解析では，特定の単球亜群で恒常的にHO-1蛋白が発現していること，これらの単球が急性炎症疾患で増加することが示され，単球/マクロファージによるHO-1産生が炎症制御に重要な役割を果たすことが明らかとされた．一方で，HO-1遺伝子導入により過剰にHO-1蛋白を発現させた場合には，むしろ細胞傷害を促進する可能性があることも示され，生体内ではHO-1産生の局在や量が巧妙に制御されていることが示唆された．最近の報告では，HO-1蛋白が制御性T細胞による免疫制御に深く関わっている可能性も示されており，HO-1産生の誘導を標的とした介入が多様な炎症性疾患に対する新たな治療戦略の一つとして期待される． Heme oxygenase (HO) plays a central role in heme metabolism. At the same time, it protects cells from injury evoked by various oxidative stresses. A detailed analysis of the first human case of HO-1 deficiency revealed that HO-1 is involved in the protection of multiple tissues and organs. It is particularly important that in vivo HO-1 production is localized to selected cell types, e.g. renal tubular epithelium, reflecting the fact that HO-1 plays particularly important protective roles in these cells. In addition to renal epithelial cells and tissue macrophages, a minor subpopulation of circulating monocytes produced low, but significant levels of HO-1 and the number of these monocytes increased during episodes of acute inflammatory illnesses, indicating that monocytes play significant roles in controlling inflammation. On the other hand, excessive level of HO-1 induced by HO-1 gene transfection led to paradoxical susceptibility of the cells to oxidative injury. These results indicated that HO-1 expression is carefully controlled in vivo with regard to its location and the magnitude. Furthermore, it has been recently shown that HO-1 is involved in the immune regulation mediated by regulatory T cells. From these findings, it seems feasible to meticulously induce HO-1 protein in vivo as a novel therapeutic intervention to control various forms of inflammatory disorders.
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| 10.
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Nasruddin ; Nakajima, Yukari ; Mukai, Kanae ; Rahayu, Heni Setyowati Esti ; Nur, Muhammad ; Ishijima, Tatsuo ; Enomoto, Hiroshi ; Uesugi, Yoshihiko ; Sugama, Junko ; Nakatani, Toshio
概要:
We investigated cold plasma effects on acute wounds of mice. The mice were classified into experimental and control grou
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ps. In the former, wounds were treated using cold plasma once daily for 1 min, and then covered with hydrocolloid dressing; wounds in the control were left to heal under hydrocolloid dressing. Daily evaluation was conducted for 15 days. General and specific staining was applied to evaluate re-epithelialization, neutrophil, macrophage, myofibroblast and transforming growth factor beta. It was found that cold plasma accelerated wound healing by 1 day. Plasma may promote the late phase of inflammation, accelerate re-epithelialization and increase wound contraction. © 2014 Elsevier GmbH. All rights reserved.
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| 11.
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Ishikawa, Kazuya ; Yagi-Nakanishi, Sayaka ; Nakanishi, Yosuke ; Kondo, Satoru ; Tsuji, Akira ; Endo, Kazuhira ; Wakisaka, Naohiro ; Murono, Shigeyuki ; Yoshizaki, Tomokazu
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Objective: The aim of this study was to clarify the role of IL-33 in tumor progression. Methods: Surgical specimens from
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81 patients with squamous cell carcinoma of the tongue were studied using immunohistochemistry. Primary tumor sections were analyzed for IL-33 and ST2 expression. To examine the influence of IL-33 on the microenvironment of the tumor, we determined the mast cell density (MCD) and microvessel density of the stroma. Results: Patients with high IL-33 expression had a significantly worse prognosis (p = 0.004). IL-33 expression was significantly elevated in patients with local and nodal recurrence (p = 0.014 and p = 0.019). ST2 expression was also associated with a worse prognosis (p = 0.024) and was significantly elevated in patients with nodal recurrence (p = 0.004). MCD was associated with worse prognosis (p = 0.038) and correlated significantly with IL-33 expression (r = 0.626, p < 0.001). Micovessels in the stroma were significantly increased in the high IL-33 group (p < 0.001). Conclusion: These data suggest that the IL-33/ST2 axis contributes to tumor aggressiveness and affects the tumor microenvironment. Immunohistochemical evaluation of IL-33 and ST2 is useful for identifying patients at a high risk for poor prognosis. © 2014 Elsevier Ireland Ltd. All rights reserved.
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| 12.
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Hayashi, Yasuhiko ; Oishi, Masahiro ; Fukui, Issei ; Sasagawa, Yasuo ; Harada, Ken-ichi ; Nakada, Mitsutoshi
概要:
Background: In Rathke cleft cysts (RCCs), inflammation by the cyst contents infrequently spreads to the surrounding stru
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ctures. Calcification, which is regarded as a result of chronic inflammation of the cyst wall, can rarely be found in RCCs. Moreover, ossification is extremely rare. Case Description: A 60-year-old woman experienced headaches, fatigue, and weight loss owing to pan-hypopituitarism. Magnetic resonance imaging revealed a mass lesion in the sellar region, which was composed of two different parts, with hypointensity anteriorly and hyperintensity posteriorly on T1-weighted image, and the rim with significant hypointensity entirely on T2-weighted image. During the transsphenoidal surgery, the cyst wall was so rigid that it was difficult to cut and remove it. The cyst contained mucinous fluid with both old and new hemorrhages, and a yellowish, elastic hard, solid nodule. Postoperative histologic diagnosis was RCC with unusual lymphocyte infiltration, massive granulation, and mature bone formation. Six months later, the fluid in the cyst reaccumulated, and the patient complained of headaches. Removal of the entire cyst wall and the aspiration of the cyst content were performed to collapse the cyst cavity and, consequently, to prevent further recurrence. Postoperatively, panhypopituitarism was unchanged and the symptoms were treated with hormonal replacement. The cyst has not recurred for 2 years after the second surgery. Conclusions: Persistent, long-term inflammation induced by the RCC content, mucin-containing fluid, and several phases of hemorrhage presumably promoted the formation of mature bone on the cyst wall and of the elastically solid nodule within the cyst. © 2016 Elsevier Inc.<br />Embargo Period 12 months
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| 13.
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Nakamoto, Yasunari ; Kaneko, Shuichi ; Fan, Hong ; Momoi, Takashi ; Tsutsui, Hiroko ; Nakanishi, Kenji ; Kobayashi, Kenichi ; Suda, Takashi
概要:
金沢大学がん研究所がん病態制御<br />A persistent immune response to hepatitis viruses is a well-recognized risk factor for hepatocellul
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ar carcinoma. However, the molecular and cellular basis for the procarcinogenic potential of the immune response is not well defined. Here, using a unique animal model of chronic hepatitis that induces hepatocellular carcinogenesis, we demonstrate that neutralization of the activity of Fas ligand prevented hepatocyte apoptosis, proliferation, liver inflammation, and the eventual development of hepatocellular carcinoma. The results indicate that Fas ligand is involved not only in direct hepatocyte killing but also in the process of inflammation and hepatocellular carcinogenesis in chronic hepatitis. This is the first demonstration that amelioration of chronic inflammation by some treatment actually caused reduction of cancer development.
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| 14.
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Nakamoto, Yasunari ; Kaneko, Shuichi ; Fan, Hong ; Momoi, Takashi ; Tsutsui, Hiroko ; Nakanishi, Kenji ; Kobayashi, Kenichi ; Suda, Takashi
概要:
A persistent immune response to hepatitis viruses is a well-recognized risk factor for hepatocellular carcinoma. However, the molecular and cellular basis for the procarcinogenic potential of the immune response is not well defined.
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Here, using a unique animal model of chronic hepatitis that induces hepatocellular carcinogenesis, we demonstrate that neutralization of the activity of Fas ligand prevented hepatocyte apoptosis, proliferation, liver inflammation, and the eventual development of hepatocellular carcinoma. The results indicate that Fas ligand is involved not only in direct hepatocyte killing but also in the process of inflammation and hepatocellular carcinogenesis in chronic hepatitis. This is the first demonstration that amelioration of chronic inflammation by some treatment actually caused reduction of cancer development.
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| 15.
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Oguma, Keisuke ; Oshima, Hiroko ; Aoki, Masahiro ; Uchio, Ryusei ; Naka, Kazuhito ; Nakamura, Satoshi ; Hirao, Atsushi ; Saya, Hideyuki ; Taketo, Makoto Mark ; Oshima, Masanobu
概要:
金沢大学がん研究所がん幹細胞研究センター<br />The activation of Wnt/β-catenin signalling has an important function in gastrointestinal tumor
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igenesis. It has been suggested that the promotion of Wnt/β-catenin activity beyond the threshold is important for carcinogenesis. We herein investigated the role of macrophages in the promotion of Wnt/β-catenin activity in gastric tumorigenesis. We found β-catenin nuclear accumulation in macrophage-infiltrated dysplastic mucosa of the K19-Wnt1 mouse stomach. Moreover, macrophage depletion in Apc Δ716 mice resulted in the suppression of intestinal tumorigenesis. These results suggested the role of macrophages in the activation of Wnt/β-catenin signalling, which thus leads to tumour development. Importantly, the conditioned medium of activated macrophages promoted Wnt/β-catenin signalling in gastric cancer cells, which was suppressed by the inhibition of tumour necrosis factor (TNF)-α. Furthermore, treatment with TNF-α induced glycogen synthase kinase 3β (GSK3β) phosphorylation, which resulted in the stabilization of β-catenin. We also found that Helicobacter infection in the K19-Wnt1 mouse stomach caused mucosal macrophage infiltration and nuclear β-catenin accumulation. These results suggest that macrophage-derived TNF-α promotes Wnt/β-catenin signalling through inhibition of GSK3β, which may contribute to tumour development in the gastric mucosa. © 2008 European Molecular Biology Organization | All Rights Reserved.
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| 16.
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Mukaida, Naofumi ; Baba, Tomohisa
概要:
Chemokines were originally identified as mediators of the inflammatory process and regulators of leukocyte trafficking.
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Subsequent studies revealed their essential roles in leukocyte physiology and pathology. Moreover, chemokines have profound effects on other types of cells associated with the inflammatory response, such as endothelial cells and fibroblasts. Thus, chemokines are crucial for cancer-related inflammation, which can promote tumor development and progression. Increasing evidence points to the vital effects of several chemokines on the proliferative and invasive properties of tumor cells. The wide range of activities of chemokines in tumorigenesis highlights their roles in tumor development and progression. © 2011 Elsevier Inc. All rights reserved.
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| 17.
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Oshima, Hiroko ; Oshima, Masanobu
概要:
Accumulating evidence has indicated that inflammatory responses are important for cancer development. Epidemiological st
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udies have shown that regular use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colon cancer development. Subsequently, mouse genetic studies have shown that cyclooxygenase (COX)-2, one of the target molecules of NSAIDs, and its downstream product, prostaglandin E 2 (PGE 2), play an important role in gastrointestinal tumorigenesis. Bacterial infection stimulates the Toll-like receptor (TLR)/MyD88 pathway in tumor tissues, which leads to the induction of COX-2 in stromal cells, including macrophages. Induction of the COX-2/PGE 2 pathway in tumor stroma is important for the development and maintenance of an inflammatory microenvironment in gastrointestinal tumors. In such a microenvironment, tumor-associated macrophages express proinflammatory cytokines, including tumor necrosis factor (TNF)-α and interleukin (IL)-6, and these cytokines, respectively, activate the nuclear factor (NF)-κB and Stat3 transcription factors in epithelial cells, as well as in stromal cells. Recent mouse studies have uncovered the role of such an inflammatory network in the promotion of gastrointestinal tumor development. Genetically engineered and chemically induced mouse tumor models which mimic sporadic or inflammation-associated tumorigenesis were used in these studies. In this review article, we focus on mouse genetic studies using these tumor models, which have contributed to the elucidation of the molecular mechanisms associated with the inflammatory network in gastrointestinal tumors, and we also discuss the role of each pathway in cancer development. The involvement of immune cells such as macrophages, mast cells, and regulatory T cells in tumor promotion is also discussed. © 2011 Springer.
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| 18.
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Mukaida, Naofumi
概要:
Chemokines are a family of structurally related cytokines with four cysteines at their well-conserved positions. Most ch
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emokines are secreted proteins with a molecular weight about 10. kDa and their α helix structure at carboxyl-terminal portion is responsible for preferential binding to proteoglycans on the vascular endothelial cells and to extracellular matrix proteins. Chemokine receptors comprise a large branch of the rhodopsin family of cell-surface G-protein-coupled receptors with seven-transmembrane domains. Chemokines bind their corresponding receptors, thereby modulating the movement and functions of their target cells, particularly leukocyte trafficking, under physiological and pathological conditions. © 2014 Elsevier Inc. All rights reserved.<br />[Book Chapter]
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| 19.
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Echizen, Kanae ; Hirose, Osamu ; Maeda, Yusuke ; Oshima, Masanobu
概要:
Cyclooxygenase-2 (COX-2) and its downstream product prostaglandin E2 (PGE2) play a key role in generation of the inflamm
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atory microenvironment in tumor tissues. Gastric cancer is closely associated with Helicobacter pylori infection, which stimulates innate immune responses through Toll-like receptors (TLRs), inducing COX-2/PGE2 pathway through nuclear factor-κB activation. A pathway analysis of human gastric cancer shows that both the COX-2 pathway and Wnt/β-catenin signaling are significantly activated in tubular-type gastric cancer, and basal levels of these pathways are also increased in other types of gastric cancer. Expression of interleukin-11, chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and CXCL5, which play tumor-promoting roles through a variety of mechanisms, is induced in a COX-2/PGE2 pathway-dependent manner in both human and mouse gastric tumors. Moreover, the COX-2/PGE2 pathway plays an important role in the maintenance of stemness with expression of stem cell markers, including CD44, Prom1, and Sox9, which are induced in both gastritis and gastric tumors through a COX-2/PGE2-dependent mechanism. In contrast, disruption of Myd88 results in suppression of the inflammatory microenvironment in gastric tumors even when the COX-2/PGE2 pathway is activated, indicating that the interplay of the COX-2/PGE2 and TLR/MyD88 pathways is needed for inflammatory response in tumor tissues. Furthermore, TLR2/MyD88 signaling plays a role in maintenance of stemness in normal stem cells as well as gastric tumor cells. Accordingly, these results suggest that targeting the COX-2/PGE2 pathway together with TLR/MyD88 signaling, which would suppress the inflammatory microenvironment and maintenance of stemness, could be an effective preventive or therapeutic strategy for gastric cancer. © 2016 Japanese Cancer Association.
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| 20.
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Echizen, Kanae ; Oshima, Hiroko ; Nakayama, Mizuho ; Oshima, Masanobu ; 越前, 佳奈恵 ; 大島, 浩子 ; 中山, 瑞穂 ; 大島, 正伸
概要:
金沢大学新学術創成研究機構ナノ生命科学研究所<br />Accumulating evidence has indicated that the inflammatory response is important for tumor pr
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omotion. However, the mechanisms underlying the induction of the inflammatory response in cancer tissues and how it promotes tumorigenesis remain poorly understood. We constructed several mouse models that develop inflammation-associated gastric and intestinal tumors and examined the in vivo mechanisms of tumorigenesis. Of note, the activation of cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway and Toll-like receptor (TLR)/MyD88 signaling cooperatively induced the generation of an inflammatory microenvironment, which is required for early-stage tumorigenesis. The inflammatory response in the stroma induces TNF-α signaling in tumor cells, and the NOX1/ROS signaling pathway is activated downstream. In addition, the inflammatory pathway induces the expression of TLR2 in tumor epithelial cells. Both the NOX1/ROS and TLR2 pathways in tumor cells contribute to the acquisition and maintenance of stemness, which is an important tumor-promoting mechanism stimulated by inflammation. We also found that inflammation promotes malignant processes, like submucosal invasion, of TGF-β signaling-suppressed tumor cells through the activation of MMP2 protease. Moreover, we showed that mutant p53 induces innate immune and inflammatory signaling in the tumor stroma by a gain-of-function mechanism of mutant p53, which may explain the “cancer-induced inflammation” mechanism. These results indicate that the regulation of the inflammatory microenvironment via the inhibition of the COX-2/PGE2 and TLR/MyD88 pathways in combination will be an effective preventive or therapeutic strategy against gastrointestinal cancer development and malignant progression, especially those carrying p53 gain-of-function mutations. © 2018 Elsevier Ltd.<br />Embargo Period 12 months
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| 21.
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北嶋, 俊輔 ; Kitajima, Shunsuke
概要:
金沢大学がん進展制御研究所<br />がん抑制遺伝子Rbの不活性化は、がんの悪性進展過程において頻繁に観察される。これまでに私達は、p53が欠損したがん細胞において、Rbの不活性化により、がん幹細胞様細胞が出現することを明らかにした。RNA
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sequenceにより遺伝子発現を解析した結果、Rb不活性化により誘導されるがん幹細胞様細胞群では炎症性サイトカインの発現が亢進していることが明らかになった。さらに遺伝子ノックダウン実験から、これら炎症性サイトカインの分泌さらにその下流のSTAT3活性化が、Rb不活性化によるがん幹細胞様細胞の誘導と炎症性がん微小環境の形成に寄与することが明らかになった。これは、Rb不活性化が、がん細胞の幹細胞性獲得というCell autonomousな作用のみならず、Non-cell autonomousな作用を介して、がんの悪性化を促進することを意味する。<br />Inactivation of Rb is frequently found during tumor progression. We found that Rb inactivation in p53 null background contributes to the acquisition of cancer stemness. RNA sequence analysis revealed that these cells exhibited signatures of inflammatory conditions. Knockdown experiments showed that sphere-forming activity induced by Rb depletion depend on activation of IL6 -STAT3 axis. Moreover, it seems that activation of STAT3 pathway induced by Rb inactivation directly cause an inflammatory tumor environment. These results are expected to provide some new insights into cell autonomous and non-cell autonomous function of Rb during tumor progression.<br />研究課題/領域番号:23701048, 研究期間(年度):2011-2012
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| 22.
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Nicholas, Barker
概要:
金沢大学医薬保健研究域医学系<br />新たな治療標的となるがん幹細胞集団を見出し、胃がん進行に対するそれらの寄与を見積もるためには、ヒト胃がんの発生を正確に模倣できる侵襲性・転移性胃がんマウスモデルの開発が喫緊の課題である。我々は、Lgr
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5陽性の胃がん細胞ががん幹細胞である可能性を検証し、胃がんの進展に対するそれらの役割を明らかにするため、炎症依存的に侵襲性胃がんを発症する新規胃がんマウスモデルを作製した。これらのマウスモデルは、将来の抗がん治療の有効性/選択性を正確に評価するためのスクリーニング方法としても非常に重要であり、得られた知見は独創的で胃がん研究分野に大きな影響を与えると予想される。<br />There is an urgent, unmet need for accurate mouse models of invasive, metastatic gastric cancer that can be used to derive important mechanistic insight into gastric cancer progression and to identify candidate cancer stem cell populations as novel therapeutic targets. We generated the first inflammation-driven mouse models of invasive gastric cancer for use in studying gastric cancer development in the stomach, with a particular focus on understanding the role of Lgr5+ stem cells and Lgr5+ cancer stem cells in this process.These mouse models will also be invaluable as screening modalities for accurately evaluating the efficacy/selectivity of future anti-cancer therapeutics. The mouse models and experimental procedures detailed here are original and will deliver results that are expected to have a major impact on the gastric cancer research field.<br />研究課題/領域番号:17H01399, 研究期間(年度):2017-04-01 – 2020-03-31<br />出典：「Developing mouse models of inflammation-driven invasive gastric cancer to reveal novel therapeutic targets」研究成果報告書 課題番号17H01399（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-17H01399/17H01399seika/)を加工して作成
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| 23.
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大島, 正伸 ; Oshima, Masanobu
概要:
Wntシグナルの亢進は胃癌発生の重要な原因のひとつであると考えられている。また、胃癌組織では、プロスタグランジン合成酵素のCOX-2とプロスタグランジンE_2(PGE_2)変換酵素のmPGES-1の発現誘導も認められており、これらにより産生
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されるPGE2が胃癌発生に重要であると考えられている。しかし、WntシグナルとPGE_2経路の相互作用については不明な点が多かった。そこで、それぞれのシグナル経路を胃粘膜上皮で活性化させた2系統のトランスジェニックマウスを作製して交配実験を行ない、各シグナルの単独および相互作用による胃癌発生への影響について研究を行なった。胃粘膜上皮でWmtシグナルを活性化したK19-Wnt1マウスでは、未分化な上皮細胞のマーカーであるTFF2の陽性細胞数が増加し、細胞分化の抑制が認められた。また、このモデルでは胃粘膜に微小隆起病変が発生し、組織学的には異形性を伴う前癌病変であった。これらは、腫瘍形成には至らなかったので、Wntシグナル亢進は発癌の引き金になり得るが、それだけでは発癌に十分ではないと考えられた。一方、胃粘膜でPGE2産生を亢進したK19-C2mEマウスは、胃粘膜上皮でCOX-2とmPGES-1を同時に発現している。このマウスでは、粘液細胞化生をともなう過形成病変が認められた。すなわち、PGE2経路は細胞増殖の亢進と分化方向の制御に重要である可能性が考えられた。しかし、PGE2シグナル亢進だけでは異形性病変は発生しなかった。多くのヒト胃癌組織ではWntシグナルとPGE2経路の双方が亢進していると考えられるので、双方のマウスモデルを交配してダブルトランスジェニックマウス(K19-Wnt1/C2mE)を作製した。その結果、異形性を伴う胃癌発生が全ての個体で認められた。したがって、WntとPGE2の双方の活性化により胃癌が発生する事が明らかとなった。<br />Accumulating evidence indicates that the Wnt signaling as well as prostaglandin E_2 (PGE_2), a downstream product of cyclooxygenase 2 (COX-2), plays a key role in gastric tumorigenesis. However, the molecular mechanism remains poorly understood how the Wnt and PGE_2 pathways contribute to gastric tumorigenesis. To investigate their roles in gastric cancer, we have generated transgenic mice activating both pathways in the gastric epithelial cells, and examined their phenotypes. First, we constructed K19-C2mE mice that expressed COX-2 and mPGES-1 in the gastric mucosa using the keratin 19 (K19) promoter. mPGES-1 is a PGE_2 converting enzyme induced simultaneously with COX-2 in a variety of cancers. K19-C2mE mice showed mucous cell metaplasia and hyperplasia in the glandular stomach with heavy macrophage accumulation. Activation of mucosal macrophages and inflammatory response were responsible for metaplastic hyperplasia in K19-C2mE mice. We next constructed K19-Wntl transgenic mice expressing Wntl in the gastric mucosa under the control of K19 promoter. K19-Wntl mice had a significant suppression of epithelial differentiation, and developed small preneoplastic lesions consisting of undifferentiated epithelial cells with macrophage accumulation. However, K19-Wntl mice did not develop gastric tumors. We then crossed K19-Wnt1 mice with K19-C2mE to obtain K19-Wnt1/C2mE compound transgenic mice. Importantly, increase of PGE_2 through induction of COX-2 and mPGES-1 in the K19-Wnt1 mice converted the preneoplastic lesions into malignant gastric tumors. These results indicate that simultaneous activation of both Wnt and PGE_2 pathways causes malignant gastric tumors. Accordingly, K19-Wntl/C2mE mouse model is a useful, tool to study the genetic mechanism of gastric carcinogenesis through activation of the Wnt and PGE_2 pathways.<br />研究課題/領域番号:17390114, 研究期間(年度):2005-2006<br />出典：「胃癌発生におけるWntシグナル亢進とCOX-2発現誘導の相互作用」研究成果報告書 課題番号17390114 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 24.
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小泉, 晶一 ; Koizumi, Shoichi
概要:
ヘムオキシゲナーゼ1(HO-1)はヘムを一酸化炭素(CO)とビリルビンとフェリチン(Feより誘導される)に代謝する律則酵素である。われわれが世界で初めて発見した「ヒトHO-1欠損」症例(1999)は2歳頃からの全身性慢性炎症が増悪し,6歳で
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死亡した。本症例のこれまでの詳細な病態解析とin vitro実験的研究によって、HO-1の、生体へのストレス防御因子としての役割を解明し、下記の研究成果を得た。(1)患児の生検材料やリンパ球細胞株でHO-1の発現が認めらないことと、HO-1遺伝子の異常から本疾患が確立された。(2)HO-1欠損症の臨床特徴は、主として造血系単球と血管内皮細胞及び腎尿細管細胞の障害に起因する。(3)HO-1欠損症では、外因性酸化ストレスによって、全身性炎症と凝固線溶系の著しい亢進を惹起し、ストレスが長期に継続すると、免疫系や凝固線溶系が消耗、破壊される。(4)単球細胞表面抗原の異常、貪食能の低下が認められた。また、CD16high/CCR2-の細胞亜群にHO-1発現が強く、この細胞群の動態は細菌性感染症とウイルス性感染症で異なっていることから、単球のHO-1発現が各種感染症の病態表現に深くかかわっていることが示唆された。さらに、単球のHb/Hp/CD163コンプレックスがHO-1誘導と強く相関することがわかった。(5)各種腎疾患の生検材料、及びin vitro細胞株の検討から、HO-1は腎尿細管上皮がストレス防御に有効に働いていることが強く示唆された。さらに尿沈さ細胞中のHO-1濃度測定は、腎尿細管傷害を観察する非侵襲的な方法として有用であろうと思われた。(6)以上、HO-1欠損症の詳細な検討は、システミックな炎症発症における新しい病態機序の解明に役立ち、そして、新しい治療法の開発に繋がるかの知れない。<br />Heme oxygenase (HO) is the rate-limiting enzyme that adds an oxygen molecule to the porphyrin ring of heme, thereby catalyzing the oxidation of heme to biliverdin/ bilirubin, free iron, and carbon monoxide (CO). By producing these metabolites, HO plays a crucial role in humans as a defense factor against a variety of oxidative stresses. The first case of human HO - 1 deficiency was reported by Yachie, et. Al. in our laboratory in 1999. A series of clinical and laboratory investigation of the patient with HO-1 deficiency revealed that (1) The boy completely lacked HO-1, genetically having a two-base-pair deletion in exon 3 of the paternal allele of the gene and a deletion of exon 2 of the maternal allele with genomic exon-deletion (1,730bp) mediated by Alu-Alu, recombination. (2) Dysfunction of both monocytes and endothelial cells was remarkably demonstrated. (2) External continuous stresses triggered excessive systemic inflammatory reactions and marked abnormalities of the coagulation/ fibrinolysis system, resulting finally in exhaustion of immune and coagulation system. (3) Morphological abnormality of monocytes and significant reduction of their surface molecules resulted in a markedly impaired phagocytosis of monocytes. Furthermore, the selective expansion of a CD16+++, CCR2- subpopulation of monocytes that preferentially produced HO-1 mRNA was shown during the acute phase of infections including both bacterial and viral infections. HO-1 production by alveolar macrophages in childhood pulmonary hypertension correlated with overexpression of CD1G3 surface molecules was also demonstrated. (4) Progressive renal tubulointerstitial injury was remarkable in the patient with HO-1 deficiency. Enhanced production of HO-lin proximal tubular epithelial cells as compared with mesangial cells was shown in variety of renal biopsy specimen as well as in vitro experiment. Recently HO-1 production by urinary tract cells and evaluation of tubulointestinal injury of the kidney was investigated by MA analysis of urinary sediments. Detailed analysis of HO-I deficiency may offer a valuable tool to understand the pathogenesis of and to develop a novel therapeutic approach to systemic inflammatory illnesses.<br />研究課題/領域番号:17390298, 研究期間(年度):2005-2007<br />出典：「ヘムオキシゲナーゼ1欠損と全身性慢性炎症に対する防御機構の破綻」研究成果報告書 課題番号17390298 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 25.
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小泉, 晶一 ; Koizumi, Shoichi
概要:
本研究は,われわれが世界で初めての新しい疾患「ヒトヘムオキシゲナーゼ1(HO-1)欠損症」を発見したことに端を発する.患児は2歳頃から,全身性慢性炎症,溶血性貧血を認め,さらに凝固,線溶系の異常亢進,高血圧も認め,6歳で頭蓋内出血で死亡した
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.本症の原因はヘモグロビンからビリベルディンへの代謝をつかさどるHO-1酵素蛋白の遺伝的欠損症であることが、遺伝子解析からも証明された.本症例のこれまでの病態解析から,本酵素は特に血液単球,腎尿細管,血管内皮の機能発現と維持などの多様な生理学的意義を有することが示唆された。(1)患児および両親のHO-1遺伝子解析から,母親アリルにエクソン2の欠損,父親アリルではエクソン3に2塩基欠損があることがわかり,患児はその複合ヘテロ接合体であることが知れた。さらに母親の染色体遺伝子を検索したところ,エクソン2を含む1,730bpにおよぶ大きな欠損が証明された。さらに,エクソン2はAluくり返し配列にはさまれる構造であることが知れ,本例のエクソン2欠損はAluくり返し配列の相同的組み換えによる配列欠失の可能性が示唆された。(2)HO-1欠損症例では単球に形態および機能異常がみられた。本研究では種々の細菌性,ウイルス感染症,および血管性病変(川崎病など)における血液細胞のHO-1発現状態を比較検討し、特に単球のHO-1発現と種々の感染症病態との関係を明らかにした。HO-1遺伝子プロモーター領域のGTレピート多型には有意差を認めなかった。(3)HO-1欠損症例では尿細管のダメージが経過とともに増悪した。そこで本研究では各種腎疾患におけるHO-1発現を免疫組織染色法、in situ hybridization法で検討した。さらにメサンギウム細胞株と比較すると、ヒト近位尿細管上皮細胞株でHO-1発現がより強く,ストレス感受性が高いことが知れた。(4)細胞株ECV304にHO-1遺伝子を導入した。低〜中等度HO-1蛋白発現株では,ヘミンや過酸化水素などのストレスを負荷すると細胞障害の抑制が認められたが、高度HO-1蛋白発現株では、逆に細胞障害の増強がみられた。このことは、HO-1蛋白発現量が多すぎても、決して防御的には働かず、かえって血管障害を増強する可能性を示唆した。将来の遺伝子治療において、HO-1遺伝子発現を恒常的ではなく、生理的なストレス誘導性とする必要があることを示唆した。<br />The first-described case of human heme oxygenase-1 (HO-1) deficiency is presented. The patient, a 6-year-old boy, similar to HO-1 knockout mice, exhibited severe growth retardation, anemia, iron deposition in renal and hepatic tissue, and vulnerability to stress-related injury with high fever.(1) The genomic analysis revealed that the boy completely lacked HO-1, having a deletion of exon 2 of the maternal allele and a two-base-pair deletion in exon 3 of the paternal allele of the gene. Further analysis revealed structural evidence of genomic exon-deletion (l,730bp) mediated by Alu-Alu recombination in this case.(2) The boy exhibited morphological abnormality of monocytes and significant reduction of their surface molecules including CD11b, CD 14, CD16 and CD36, resulting in a markedly impaired phagocytosis of monocytes. We investigated the importance of monocyte HO-1 production in two in vivo model systems. In acute febrile illnesses monocytes are activated with simultaneous increase o f HO-1 production. In addition, we also examined HO-1 production by alveolar macrophages in childhood pulmonary hypertension, showing well correlation of the level of HO-1 with the degree of pulmonary hypertension.(3) Renal mesangial change in glomerular capillary-wall thickness was shown in the three consecutive biopsy specimens in this case. Tubulointerstitial injury, with tubular dilatation and/or atrophy, interstitial fibrosis, and inflammatory cell infiltration advanced progressively. Electron microscopic examination showed widespread endothelial detachment and subendothelial deposits of an unidentifiable material. Furthermore, we compared the patterns of HO-1 expression and the responses to stress-induced cytotoxicity by primary cultured human mesangial cells (hMCs) and proximal tubular epithelial cells (hTECs) in vitro. The hTECs were shown to be more susceptible to oxidative stress and significantly more dependent on HO-1 expression than the hMCs.(4) We transfected HO-1 gene to die ECV304 cells with a minimal level of HO-1 expression. The high HO-1-expressed cells showed more increase of cell death by H2O2 than die low HO-1-expressed one, indicating that the high expression of HO-1 was not always a good prognostic factor for prevention of stress-induced injuries.From these data based on the first human case of HO-1 deficiency, multilateral physiological functions of die HO-1 enzyme were newly evidenced.<br />研究課題/領域番号:13470160, 研究期間(年度):2001-2002<br />出典：「ヘムオキシゲナーゼ1(HO-1)の多面的生理学的意義: HO-1欠損症からの学習」研究成果報告書 課題番号13470160 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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| 26.
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小泉, 晶一 ; Koizumi, Shoichi
概要:
本研究の動機は,最近われわれが従来全く報告のない新しい疾患「ヘムオキシゲナーゼ1(HO-1)欠損症」の症例を発見したことによる.世界最初の症例である.患児は2歳頃から,発熱,白血球増多,関節炎を伴う慢性炎症,肝腫大,赤ワイン色血清,赤血球破
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砕を伴う溶血性貧血を認め,さらに凝固,線溶系の異常亢進,vWF因子,トロンボモデュリン,血管内皮由来サイトカインの高値から毛細血管内皮細胞障害が疑われた.高血圧を認め,6歳で死亡した.高脂血症も認めた.本症例では溶血が存在するにもかかわらず,低ビリルビン血症,高ハプトグロビン血症がみられることが病態解明のきっかけとなり,検索の結果,本症の原因はヘモグロビンからビリベルディンへの代謝をつかさどるHO-1酵素蛋白の遺伝的欠損症であることが解明された.HO-1は感染,低酸素などにより強く誘導発現され,生体に対する酸化ストレス防御因子として重要である.さらにHO-1はCOを合成し,COは微小循環を確保し,毛細血管内皮の保護とその機能恒常性の維持に重要である.したがって本例にみられる多彩な症状は,HO-1欠損による血管内皮細胞障害,血液細胞障害やストレス防御機構の破綻に起因する可能性が高い.これまでに本症例の解析,および関連する研究で次の点が明らかになった.1)HO-1遺伝子解析から,母親ではエクソン2の欠損,父親ではエクソン3に2塩基欠損があることがわかり,患児はその複合へテロ接合体であった.さらに母親アリルにはAlu-Alu関連遺伝子再構成に基づく,エクソン2を含む大きな染色体遺伝子の部分欠損が証明された.2)正常HO-1遺伝子を含むレトロウイルスベクターの作成し,患児細胞株LCLへ遺伝子導入したところ,HO-1蛋白発現と機能の部分的正常化がみられた.ただしこのHO-1発現は恒常的で,生理的にみられるようなストレス誘導性発現ではなかった.3)本症例では特に,尿細管の傷害が経過とともに増悪した.電顕では血管内皮の剥離と異常物質の沈着が認められた.4)血管内皮細胞株ECV304にHO-1遺伝子をレトロウイルスベクターを用いてトランスフェクトし,HO-1蛋白発現の異なる種々の細胞株が樹立された.それらの細胞株のストレスに対する抵抗性を検討した.<br />The first-described case of heme oxygenase-1 (HO-1) deficiency is presented. The patient, a 6-year-old boy, completely lacks HO-1, having a deletion of exon 2 of the maternal allele and a two-base-pair deletion in exon 3 of the paternal allele of the gene. Further analysis revealed structural evidence of genomic exon-deletion mediated by Alu-Alu recombination in this case. Similar to recently described HO-1 knockout mice, the boy exhibits severe growth retardation, anemia, iron deposition in renal and hepatic tissue, and vulnerability to stress-related injury. Mesangial change in glomerular capillary-wall thickness was shown in the three consecutive biopsy specimens. Electron microscopic examination showed widespread endothelial detachment and subendothelial deposits of an unidentifiable material. It was striking that tubulointerstitial injury, with tubular dilatation and/or atrophy, interstitial fibrosis, and inflammatory cell infiltration, advanced progressively. In addition, the boy exhibited morphological abnormality of monocytes and significant reduction of their surface molecules including CD11b, CD14, CD16 and CD36, resulting in a markedly impaired phagocytosis of monocytes.Heme oxygenase, which catalyzes the conversion of heme into carbon monoxide and biliverdin, plays an important anti-inflammatory role in oxidative injury. The two known isoforms differ in their expression pattern, with HO-2 constitutively expressed in brain and testis, and HO-1 expressed ubiquitously at low levels, although it is rapidly induced following various stresses. The importance of the current work may lie less in its being the first described case of human HO-1 deficiency than in the clues it provides to the normal functions of this important enzyme.<br />研究課題/領域番号:11470170, 研究期間(年度):1999-2000<br />出典：「ヘムオキシゲナーゼ1欠損症の発見:血管内皮傷害病態の解明と遺伝子治療の基礎的研究」研究成果報告書 課題番号11470170(KAKEN：科学研究費助成事業データベース（国立情報学研究所）) 本文データは著者版報告書より作成
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浅野, 雅秀 ; Asano, Masahide
概要:
金沢大学学際科学実験センター<br />細胞の増殖と分化には細胞間の相互作用が重要であり,細胞表面の糖鎖を介した相互作用はその中でも重要な機構の一つである。我々はβ-1,4-ガラクトース転移酵素-I(β4GalT-I)遺伝子KOマウスを作成
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して,生体内でのガラクトース糖鎖の役割を解析してきた。しかし,最近β4GalTが7つの遺伝子からなるファミリーを形成していることがわかり,β4GalT遺伝子群に役割分担があることがわかってきた。そこで,β4GalT-I KOマウスの糖鎖構造を詳細に解析して,β1,4-結合のGalを定量し、糖鎖生合成における細胞種ごとのβ4GalT-I遺伝子の寄与を検討した。次に、β4GalTが生合成に関与することが知られているセレクチンのリガンド糖鎖について解析し、その生合成におけるβ4GalT-Iの寄与を検討した。さらに、セレクチンが関与する炎症反応について、β4GalT-I KOマウスの応答性を解析し、β4GalT-I遺伝子の欠損が炎症反応に与える影響を明らかにした。また、皮膚創傷治癒過程におけるβ4GalT-I遺伝子欠損の影響を解析した。以上の結果、β4GalT-Iはセレクチンのリガンド糖鎖の生合成に重要な役割を担っており、β4GalT-I KOマウスでは、その欠損のために炎症反応の減弱や皮膚創傷治癒過程の遅延が生じたと考えられた。以上の解析はすべて交雑系のβ4GalT-I KOマウスを用いて行ったが、一方、近交系のβ4GalT-I KOマウスは胎生後期に致死となることを明らかにした。致死となる数日前から胎仔よりはむしろ胎盤の成長遅延が顕著に認められ、胎盤の異常が致死の原因であることが示唆された。このようにマウスの遺伝的背景により致死性が変化する理由として、他のβ4GalT遺伝子群による相補が考えられたので、他のβ4GalT遺伝子のKOマウスも作製して両者の役割分担の解析を現在進めている。<br />Cell-to-cell, interactions are important for cell growth and differentiation. The interaction through cell surface carbohydrates is one of indispensable mechanisms among them. We have been studying on the role of carbohydrates in vivo by generating a gene knockout mouse deficient in β-1.4-galactosyhransferase-I(β4GalT-I). β4GalTs are recently found to form the gene family consisting of 7 genes, which have their own roles.We analyzed carbohydrate structures of β4GalT-I KO mice in detail. Contribution of β4GalT-I gene to the biosynthesis of carbohydrates of various cell types was estimated by measuring Gal residues in the β1,4-linkage. Next, carbohydrate ligands of selectins, which are known to be synthesized by β4GalTs and other glycosyltransferases, were analyzed in β4GalT-I KO mice. Contribution of β4GalT-I gene to their biosynthesis was also estimated. Furthermore, Inflammatory responses of β4GalT-I KO mice and the effect of β4GalT-I deficiency were examined. In addition, the effect of β4GalT-I deficiency on skin wound healing was examined. Our results indicated that β4GalT-I plays an important role in the biosynthesis of carbohydrate ligands of selectins and their deficiency results in reduction of inflammatory responses and delayed wound healing in β4GalT-I KO mice.While these results were obtained using β4GalT-I KO mice on mixed genetic backgrounds, we found β4GalT-I KO mice on inbred background to be lethal during late embryogenesis. Since growth retardation of the placenta rather than the embryo was remarkable several days before its death, the defect of placenta was suggested to be a cause of the embryonic lethality. Since the reason of changeable lethality depending on genetic background might be a compensatory activity by other β4GalTs, gene knockout mice deficient in another β4GalT gene were generated. Studies on elucidating the role of these p4GalT genes are in progress.<br />研究課題/領域番号:13480280, 研究期間(年度):2001 – 2003<br />出典：「ノックアウトマウスを用いたガラクトース転移酵素遺伝子群の役割分担の解明」研究成果報告書 課題番号13480280（KAKEN：科学研究費助成事業データベース（国立情報学研究所））（https://kaken.nii.ac.jp/ja/report/KAKENHI-PROJECT-13480280/134802802003kenkyu_seika_hokoku_gaiyo/)を加工して作成
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