記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osteopontin (OPN) is elevated during the progression of experimental autoimmune uveoretinitis (EAU) in C57BL/6 (B6) mice. Furthermore, EAU symptoms are ameliorated in OPN knockout mice or in B6 mice treated with anti-OPN antibody (M5). Recently, OPN has been shown to promote the Th1 response not only in the extracellular space as a secretory protein but also in cytosol as a signaling component. Thus, we attempted to reduce OPN in both compartments by using a small interfering RNA (siRNA) targeting the OPN coding sequence (OPN-siRNA). EAU was induced in B6 mice by immunization with human interphotoreceptor retinoid-binding protein (hIRBP) peptide sequence 1-20. The OPN- or control-siRNA was administered with hydrodynamic methods 24 h before and simultaneously with immunization (prevention regimen). When plasma OPN levels were quantified following siRNA administration with the prevention regimen, the level in the OPN-siRNA-treated group was significantly lower than that in the control-siRNA-treated group. Accordingly, the clinical and histopathological scores of EAU were significantly reduced in B6 mice when siRNA caused OPN blockade. Furthermore, TNF-alpha, IFN-gamma, IL-2, GM-CSF and IL-17 levels in the culture supernatants were markedly suppressed in the OPN-siRNA-treated group, whereas the proliferative responses of T lymphocytes from regional lymph nodes against immunogenic peptides was not significantly reduced. On the other hand, the protection was not significant if the mice received the OPN-siRNA treatment on day 7 and day 8 after immunization when the clinical symptoms appeared overt (reversal regimen). Our results suggest that OPN blockade with OPN-siRNA can be an alternative choice for the usage of anti-OPN antibody and controlling uveoretinitis in the preventive regimen.

DOI： 10.1016/j.exer.2009.09.008

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osteopontin is critically involved in rheumatoid arthritis; however, the molecular cross-talk between osteopontin and joint cell components that leads to the inflammatory joint destruction is largely unknown. We found that not only osteopontin but also tenascin-C and their common receptor, alpha(9) integrin, are expressed at arthritic joints. The local production of osteopontin and tenascin-C is mainly due to synovial fibroblasts and, to a lesser extent, synovial macrophages. Synovial fibroblasts and macrophages express alpha(9) integrin, and autocrine and paracrine interactions of alpha(9) integrin on synovial fibroblasts and macrophages and its ligands contribute differently to the production of proinflammatory cytokines and chemokines. alpha(9) integrin is also involved in the recruitment and accumulation of inflammatory cells. Inhibition of alpha(9) integrin function with an anti-alpha(9) integrin Ab significantly reduces the production of arthrogenic cytokines and chemokines and ameliorates ongoing arthritis. Thus, we identified alpha(9) integrin as a critical intrinsic regulator that controls the development of autoimmune arthritis.

DOI： 10.4049/jimmunol.0900725

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osteopontin (OPN) contains at least two major integrin recognition domains, Arg159-Gly-Asp161 (RGD) and Ser162-Val-Val-Tyr-Gly-Leu-Arg168 (SVVYGLR), recognized by alphavbeta3 and alpha5beta1 and alpha4 and alpha9 integrins, respectively. OPN is specifically cleaved by thrombin and matrix metalloproteinase (MMP)-3 or MMP-7 at a position of Arg168/Ser169 (R/S) and Gly166/Leu167 (G/L), respectively. We in this study examined the requirement of residues within SVVYGLR for the alpha4 and alpha9 integrin recognition and how MMP-cleavage influences the integrin recognition. The residues, Val164, Tyr165, and Leu167 are critical for alpha4 and alpha9 integrin recognition in both cell adhesion and cell migration. The residue Arg168 is additionally required for alpha9 integrin recognition in cell adhesion and this explains why alpha9 integrin binds to only thrombin cleaved form of OPN. alpha4 integrin is able to bind to SVVYG (MMP-cleaved form of RAA OPN-N half), while alpha9 integrin is not, supporting the above notion that Arg168 is additionally required for alpha9 integrin-mediated cell adhesion. The residue Val163 is important for alpha4, but not for alpha9 integrin recognition in cell migration. Importantly, we found that the replacement of Arg168 by Ala (R168A mutant) induces the augmentation of cell migration via alpha4 and alpha9 integrins.

DOI： 10.1016/j.matbio.2008.10.002

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Invariant natural killer T (iNKT) cells belong to a subset of lymphocytes bridging innate and acquired immunity. We demonstrated that osteopontin (OPN) is involved in the activation of iNKT cells. In the present work, we examined whether OPN affects development and function of iNKT cells. We found that the number of peripheral iNKT cells was significantly reduced in OPN-deficient mice compared with wild-type mice. Although the number of thymic iNKT cells was not different between WT and OPN-deficient mice, intrathymic iNKT cell maturation was impaired in OPN-deficient mice. iNKT cell function was also significantly altered in OPN-deficient mice, as evidenced by (i) deficient down-regulation of iNKT cell receptor, (ii) reduction of IL-4 production while preserving production of IFN-gamma, and (iii) reduction of Fas ligand (FasL) expression, leading to reduced Fas/FasL-dependent cytotoxicity against hepatocytes. Importantly, activation of the transcription factors NFAT2 (nuclear factor of activated T cells 2) and GATA-3 was impaired, whereas activation of T-bet was preserved in iNKT cells of OPN-deficient mice. These data collectively indicate that OPN plays a pivotal role not only in the development, but also in the function of iNKT cells.

DOI： 10.1073/pnas.0806089105

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osteopontin (OPN) is a T helper type 1 immunoregulatory cytokine that plays a critical role in various inflammatory disorders. OPN exerts proinflammatory reactions through interaction with integrin receptors. OPN function can be modulated by protease digestion. However, the molecular mechanisms that regulate OPN function in vivo have not been elucidated. There are two putative heparin-binding domains (HBDs) within the OPN molecule, which may bind both heparin and heparin-like glycosaminoglycans such as syndecan. We show that expression of OPN and syndecan-4 is significantly up-regulated after concanavalin-A (ConA) injection. Syndecan-4 binds to one of the HBDs of OPN, which overlaps with the thrombin cleavage site of OPN. When OPN is associated with syndecan-4, syndecan-4 masks both the thrombin cleavage and the integrin binding sites within OPN. Importantly, syndecan-4-deficient (Syn4KO) mice are more susceptible to hepatic injury, and the thrombin-cleaved form of OPN is significantly elevated in Syn4KO mice as compared with wild-type mice after ConA injection. Finally, we demonstrate that administration of purified syndecan-4 protects mice from ConA-induced hepatic injury. Thus, syndecan-4 is a critical intrinsic regulator of inflammatory reactions via its effects on OPN function and is a potential novel therapeutic tool for treating inflammatory diseases.

PubMed

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記述言語：日本語   出版者・発行元：日本NP学会  

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記述言語：日本語   出版者・発行元：国立病院総合医学会  

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記述言語：日本語   出版者・発行元：日本臨床外科学会  

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記述言語：日本語   出版者・発行元：北海道外科学会  

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記述言語：日本語   出版者・発行元：日本消化器病学会-北海道支部  

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開催年月日： 2006年7月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2004年12月

記述言語：日本語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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出願人：生化学工業株式会社, 株式会社ジーンテクノサイエンス, 独立行政法人産業技術総合研究所

出願番号：特願2010-181658  出願日：2010年8月

公開番号：特開2010-263917  公開日：2010年11月

特許番号/登録番号：特許第5249998号  登録日：2013年4月 

J-GLOBAL

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出願人：生化学工業株式会社, 株式会社ジーンテクノサイエンス

出願番号：特願2010-181658  出願日：2010年8月

公開番号：特開2010-263917  公開日：2010年11月

J-GLOBAL

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出願人：株式会社ジーンテクノサイエンス

出願番号：特願2006-332850  出願日：2006年12月

公開番号：特開2008-142011  公開日：2008年6月

J-GLOBAL

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出願人：生化学工業株式会社, 株式会社ジーンテクノサイエンス

出願番号：特願2005-114424  出願日：2005年4月

公開番号：特開2005-323591  公開日：2005年11月

特許番号/登録番号：特許第4589794号  登録日：2010年9月 

J-GLOBAL

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出願人：生化学工業株式会社, 株式会社ジーンテクノサイエンス

出願番号：特願2005-114424  出願日：2005年4月

公開番号：特開2005-323591  公開日：2005年11月

J-GLOBAL

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種別：講演会

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種別：セミナー・ワークショップ

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