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論文
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Maruyama, Atsushi ; Itoh, Ken
概要:
NF-E2-related factor 2 （Nrf2） regulates the coordinate induction of phase 2 detoxifying and antioxidantenzymes in respon
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se to xenobiotics and oxidative stress via antioxidant responsive element. Nrf2 knockout mice arehighly susceptible to the acute toxicity generated by acetaminophen, butylated hydroxytoluene or hyperoxia and tocarcinogenesis induced by benzo[a]pyrene. Recently, it becomes increasingly evident that Nrf2 also plays essential rolesin the protection against infl ammation. Nrf2 regulates the infl ammation during carrageenin-induced pleurisy and lunginfl ammation, wound healing in skin, and dextran sulfate-induced colitis. Nrf2 knockout mice are also susceptible toendotoxin-induced septic shock and allergen-induced asthma. Using carrageenin-induced pleurisy and porcine neutrophilelastase-induced lung injury models, we proposed that this anti-infl ammatory action of Nrf2 relies on the activities inmacrophages. In macrophages, Nrf2 modulates the infl ammatory response by up-regulating a range of anti-oxidative andanti-infl ammatory enzymes, such as CD36 and secretory leukoprotease inhibitor（ SLPI）. CD36 is a macrophage classB scavenger receptor involved in the uptake of apoptotic neutrophils and microorganisms such as Staphylococcus aureus.Thus, Nrf2 may play important roles in the protection of infl ammation and innate immune response.
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| 2.
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論文
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Sashinami, Hiroshi ; Takagaki, Keiichi ; Nakane, Akio
概要:
Proteoglycans （PGs） are complex glycohydrates, which are widely distributed in connective tissues andon the cell surface
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of mammalian tissues. We investigated the effect of PG extracted from salmon cartilage oncytokine responses to stimulation with heat-killed Escherichia coli（ HKEC） in a mouse macrophage cell line, RAW264.7.PG exhibited the suppression of tumor necrosis factor（ TNF）-α production and enhancement of interleukin（ IL）-10production compared with chondroitin 4 sulfate（ C4S） and chondroitin 6 sulfate（ C6S）. PG, C4S and C6S suppressedHKEC-induced Toll-like receptor 4（ TLR4） and inducible nitric oxide synthase（ iNOS） expression dose-dependentlyand the PG showed the strongest suppressive effect among 3 compounds. Only PG dramatically up-regulated theexpression of signal transducers and activators of transcription 3（ STAT3） and the phosphorylation of STAT3 in mousemacrophages. Our results showed strong suppression of PG on infl ammatory response and suggested that the novelinteraction might exist between the extracellular matrix and immune system.
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| 3.
論文 |
論文
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Kudo, Fujimi ; Nishiguchi, Naoki ; Ito, Kyoko ; Nakano, Manabu ; Ito, Koichi
概要:
The P2Y14 receptor is activated by UDP-glucose （UDPG）, which is a well-known glycosyl donor that participates in the bio
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synthesis of carbohydrates, and is widely expressed in immune cells. During inflammation and mechanical stress, damaged cells release nucleotides, including ATP and UDPG, as danger signals that act as P2Y receptor agonists. These nucleotide-induced signals participate in the regulation of immune responses. In this study, to investigate P2Y14 expression further, we performed flow cytometric analysis using an anti-P2Y14 monoclonal antibody. The results indicated that P2Y14 is expressed in murine immune cells, including T cells, B cells, monocytes, granulocytes, and CD11bhigh macrophages. Interestingly, the expression levels of P2Y14 differed between immature and mature monocytes, and in CD11bhigh macrophages, P2Y14 was gradually downregulated as peritonitis was terminated. The expression of CD11b is reduced by the efferocytosis of apoptotic neutrophils during peritonitis, and the induced CD11blow macrophages, which emerge in the resolution of peritonitis, play an important role in the termination of inflammation. Consistent with this observation, we revealed that administration of UDPG to mice with induced peritonitis increased the number of CD11blow macrophages. As P2Y14 is expressed in CD11bhigh macrophages but not in CD11blow macrophages, UDPG may participate in the conversion to the CD11blow phenotype. These data suggest a novel regulatory pathway of the inflammatory response via P2Y14 expressed on macrophages.
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| 4.
学位論文 |
学位
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Kamata, Kosuke ; Mizukami, Hiroki ; Inaba, Wataru ; Tsuboi, Kentaro ; Tateishi, Yoshinori ; Yoshida, Taro ; Yagihashi, Soroku
概要:
Aims: Islet amyloid is a hallmark in type 2 diabetic subjects, but its implication in clinical features and development of islet pathology is still unclear.Methods: From 118 autopsy cases with type 2 diabetes, 26 cases with
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islet amyloid deposition (DA+) were selected. Twenty diabetic subjects without obvious amyloid deposition (DA ) matched for the age and diabetes duration and 20 non-diabetic subjects (ND) served for comparison. We examined the severity of amyloid deposition and its relationships with population of endocrine cells, expression of cell damage markers or macrophage infiltration. Correlation of clinical profile with islet pathology was also sought on the subset of the investigated patients.Results: b-Cell volume density was nearly 40% less in DA+ and 20% less in DA when compared to ND. Severity of amyloid deposition correlated with reduced volume densities of b-cell and a-cell, and increased body mass index (BMI), but not with duration of diabetes, age or HbA1c. Amyloid-rich islets contained an increased number of macrophages mixed with b-cells with oxidative stress-related DNA damage, characterized by gH2AX expression, and suppressed (pro)insulin mRNA expression.Conclusions: In Japanese type 2 diabetic patients, islet amyloid was more common with severe b-cell loss and high BMI, associated with macrophage infiltration.
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| 5.
論文 |
論文
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Tanaka, Nahoko ; Hiraga, Hiroto ; Sakuraba, Hirotake ; Murai, Yasuhisa ; Maeda, Takato ; Watanabe, Rina ; Ota, Shinji ; Akemoto, Yui ; Hasui, Keisuke ; Yoshida, Shukuko ; Asano, Krisana ; Nakane, Akio ; Fukuda, Shinsaku
概要:
Vitamin A is essential for maintenance of homeostasis, and it also regulates various immune mechanisms.Listeria monocyto
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genes is a gram-positive bacillus that invades the cytoplasm of phagocytes and performs intracellular multiplication, and is often used as a tool for functional analysis of macrophages. In this study, we investigated the changes of macrophages under vitamin A deficiency（ VAD） using L. monocytogenes. During L. monocytogenes infection,apoptosis was increased in CD11b-positive splenocytes of VAD mice compared with vitamin A sufficient （VAS）mice. A similar result was obtained with peritoneal exudate cells （PECs）. Significant increase of apoptosis due to the administration of Ro41-5253, an inhibitor of retinoic acid receptor, was also observed in the macrophage cell line RAW264.7. Furthermore, in VAD mice, the number of bacteria in the spleens and livers was significantly increased.These results suggest that excessive apoptosis of macrophages occurs under VAD condition, leading to impaired host resistance to L. monocytogenes. Taken together, vitamin A contributes to the maintenance of homeostasis by regulating macrophage functions, indicating the importance of vitamin A supplementation.
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