Tatara Y.,Tohoku University |
Tatara Y.,Hirosaki University |
Terakawa T.,Tohoku University |
Terakawa T.,Effector Cell Institute Inc. |
Uchida T.,Tohoku University
Bioscience, Biotechnology and Biochemistry | Year: 2010
To determine the role of Pin1 in the neurotransmission pathway, Pin1-binding proteins in mouse brain extract were identified. The Pin1-binding proteins were extracted from mouse brain homogenate, and the trypsin-digested peptides were analyzed by nano-liquid chromatography tandem mass spectrometry (LC-MS/ MS). Proteins that involve the neurotransmission pathway, such as synapsin I, synapsin II, and calcium/ calmodulin-dependent protein kinase type II (CaMKII), were identified in a Mascot search. Pull-down and immunoprecipitation assay indicated that Pin1 binds CaMKII in a phosphorylation-specific manner. It was assumed that Pin1 participates in the neurotransmission pathway involving the phosphorylation signal by CaMKII.
Kanegasaki S.,Effector Cell Institute Inc. |
Kanegasaki S.,Yeungnam University |
Matsushima K.,University of Tokyo |
Shiraishi K.,University of Tokyo |
And 3 more authors.
Cancer Research | Year: 2014
Radiotherapy can produce antitumor benefits beyond the local site of irradiation, an immune-based phenomenon known as the abscopal effect, but the mechanisms underlying these benefits are poorly understood. Preclinical studies of ECI301, a mutant derivative of macrophage inhibitory protein-1α, have shown that its administration can improve the antitumor effects of radiotherapy in a manner associated with a tumorindependent abscopal effect. In this article, we report that i.v. administration of ECI301 after intratumoral injection of tumor cell lysates can inhibit tumor growth, not only at the site of injection but also at nontreated sites. Effects of the tumor lysate were further recapitulated by i.v. administration of the alarmins HSP70 or HMGB1, but not HSP60, and combinations of ECI301 + HSP70 were sufficient to inhibit tumor growth. Although injection of ECI301 + HMGB1 did not inhibit tumor growth, we found that administration of a neutralizing HMGB1 antibody neutralized the cooperative effects of ECI301 on tumor irradiation. Moreover, mice genetically deficient in TLR4, an immune pattern receptor that binds alarmins, including HMGB1 and HSP70, did not exhibit antitumor responses to irradiation with ECI301 administration. Although ECI301 was cleared rapidly from peripheral blood, it was found to bind avidly to HSP70 and HMGB1 in vitro. Our results suggest a model in which sequential release of the alarmins HSP70 and HMGB1 from a tumor by irradiation may trap circulating ECI301, thereby licensing or restoring tumor immunosurveillance capabilities of natural killer cells or CD4 and CD8 T cells against tumor cells that may evade irradiation. © 2014 American Association for Cancer Research.
Biragyn A.,U.S. National Institute on Aging |
Bodogai M.,U.S. National Institute on Aging |
Olkhanud P.B.,U.S. National Institute on Aging |
Denny-Brown S.R.,U.S. National Institute on Aging |
And 6 more authors.
Journal of Immunotherapy | Year: 2013
Despite significant attractiveness of antisense oligonucleotide/RNAi technology, its clinical application has been precluded by a lack of methods for targeted delivery and transduction of primary immune cells in vivo. Here, we devised a chemokine CCL17-based strategy (TARC-arp) that transiently silences expression of genes in immune cells by delivering inhibitory oligonucleotides through their chemokine receptors. In modeling studies using mice with established 4T1.2 breast cancer, we show that IL10 produced by CCR4 cells, in particular FoxP3 regulatory T cells (Tregs), plays an important role in lung metastasis. As such, TARC-arp-mediated silencing of IL10 or FoxP3 in CCR4 Tregs is sufficient to block lung metastasis. Thus, we provide a simple solution that circumvents the problems of RNAi use in vivo, indicating that a disease outcome can be successfully controlled by delivering inhibitory oligonucleotides with chemokines to inactivate a selective subset of immune cells. © 2013 by Lippincott Williams & Wilkins.
Yoshiura C.,University of Tokyo |
Kofuku Y.,University of Tokyo |
Ueda T.,University of Tokyo |
Mase Y.,University of Tokyo |
And 7 more authors.
Journal of the American Chemical Society | Year: 2010
CC-chemokine receptor 5 (CCR5) belongs to the G protein-coupled receptor (GPCR) family and plays important roles in the inflammatory response. In addition, its ligands inhibit the HIV infection. Structural analyses of CCR5 have been hampered by its instability in the detergent-solubilized form. Here, CCR5 was reconstituted into high density lipoprotein (rHDL), which enabled CCR5 to maintain its functions for >24 h and to be suitable for structural analyses. By applying the methyl-directed transferred cross-saturation (TCS) method to the complex between rHDL-reconstituted CCR5 and its ligand MIP-1α, we demonstrated that valine 59 and valine 63 of MIP-1α are in close proximity to CCR5 in the complex. Furthermore, these results suggest that the protective influence on HIV-1 infection of a SNP of MIP-1α is due to its change of affinity for CCR5. This method will be useful for investigating the various and complex signaling mediated by GPCR, and will also provide structural information about the interactions of other GPCRs with lipids, ligands, G-proteins, and effector molecules. © 2010 American Chemical Society.
Shiraishi K.,University of Tokyo |
Nakagawa K.,University of Tokyo |
Niibe Y.,Kitasato University |
Ishiwata Y.,University of Tokyo |
And 5 more authors.
Current Signal Transduction Therapy | Year: 2010
The abscopal effect is a potentially important phenomenon as a topic for basic research on tumor control and clinical oncology. Although it has been described in various malignancies, it is a rarely recognized clinical event. This phenomenon may arise mainly as a result of an activated immune system mediated through cytokines. Until recently, the abscopal effect referred to distant effects observed after local radiation therapy. However, some investigators argue that the term should now be used interchangeably with the "distant bystander effect." From several aspects, including the distant bystander effects of other local therapies, we discuss the poorly researched but potentially intriguing abscopal effect that follows radiation therapy. Recently, experimentally-induced abscopal effects have been reported. Those reports show favorable inhibition of tumor growth not only at the irradiated site, but also at areas distant from the irradiated site using experimental protocols designed to induce reproducible abscopal effects. If consistent induction of the abscopal effect could be potentiated by intravenous administration of an immunostimulant, oncologists will seize upon the application of this effect for clinical use. Though the abscopal effect is still extremely controversial in view of the data now available, it can be hoped that translational research may offer a new concept for cancer therapy, namely, chemokine administration following local irradiation, leading to development of novel therapies for the treatment of advanced or metastatic cancer. © 2010 Bentham Science Publishers Ltd.