JunB is required for CD8+ T cell responses to acute infections.

Basic-leucine zipper transcription factor ATF-like (BATF) and interferon regulatory factor 4 (IRF4) are crucial transcription factors for generation of cytotoxic effector and memory CD8+ T cells. JunB is required for expression of genes controlled by BATF and IRF4 in CD4+ T cell responses, but the role of JunB in CD8+ T cells remains unknown. Here, we demonstrate that JunB is essential for cytotoxic CD8+ T cell responses.

The CCR4-NOT deadenylase complex safeguards thymic positive selection by down-regulating aberrant pro-apoptotic gene expression.

A repertoire of T cells with diverse antigen receptors is selected in the thymus. However, detailed mechanisms underlying this thymic positive selection are not clear. Here we show that the CCR4-NOT complex limits expression of specific genes through deadenylation of mRNA poly(A) tails, enabling positive selection.

Prostaglandin E Receptor 4 Antagonist in Cancer Immunotherapy: Mechanisms of Action.

A highly expressed prostaglandin E (PGE) in tumor tissues suppresses antitumor immunity in the tumor microenvironment (TME) and causes tumor immune evasion leading to disease progression. In animal studies, selective inhibition of the prostaglandin E receptor 4 (EP4), one of four PGE receptors, suppresses tumor growth, restoring the tumor immune response toward an antitumorigenic condition. This review summarizes PGE/EP4 signal inhibition in relation to the cancer-immunity cycle (C-IC), which describes fundamental tumor-immune interactions in cancer immunotherapy.

Transcriptional Regulation of Differentiation and Functions of Effector T Regulatory Cells.

Foxp3-expressing regulatory T (Treg) cells can suppress the activity of various types of immune cells and play key roles in the maintenance of self-tolerance and in the regulation of immune responses against pathogens and tumor cells. Treg cells consist of heterogeneous subsets that have distinct phenotypes and functions. Upon antigen stimulation, naïve-like thymus-derived Treg cells, which circulate in secondary lymphoid organs, can differentiate into effector Treg (eTreg) cells and migrate to and control immune homeostasis of peripheral tissues.

JunB regulates homeostasis and suppressive functions of effector regulatory T cells.

Foxp3-expressing CD4 regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. T-cell receptor (TCR)-dependent induction of the transcription factor IRF4 is essential for eTreg differentiation, but how IRF4 activity is regulated in Treg cells is still unclear. Here we show that the AP-1 transcription factor, JunB, is expressed in eTreg cells and promotes an IRF4-dependent transcription program.

JunB is essential for IL-23-dependent pathogenicity of Th17 cells.

CD4 T-helper cells producing interleukin-17 (IL-17), known as T-helper 17 (T17) cells, comprise heterogeneous subsets that exhibit distinct pathogenicity. Although pathogenic and non-pathogenic T17 subsets share a common RORγt-dependent T17 transcriptional programme, transcriptional regulatory mechanisms specific to each of these subsets are mostly unknown. Here we show that the AP-1 transcription factor JunB is critical for T17 pathogenicity.

[Transcription factors in the development of myeloid cells].

Hematopoietic stem cells give rise to various blood cell types with diverse functions, although these different cell types harbor essentially identical genome sequences. The basis for this cell type diversity is the establishment of specific gene expression patterns through transcription factor regulation. Transcription factors recognize and bind to specific nucleotide sequences in target genes and recruit chromatin modifiers to alter the epigenetic status of these genes, thereby controlling their expression.

Regulation of myelopoiesis by the transcription factor IRF8.

Interferon regulatory factor-8 (IRF8) is a transcription factor expressed in hematopoietic cells, particularly in mononuclear phagocytes [monocytes/macrophages and dendritic cells (DCs)] and their progenitors. Various studies have demonstrated that IRF8 is essential for the development of monocytes, DCs, eosinophils, and basophils. Conversely, IRF8 suppresses the generation of neutrophils.

Transcription factor IRF8 plays a critical role in the development of murine basophils and mast cells.

Basophils and mast cells play critical roles in host defense against pathogens and allergic disorders. However, the molecular mechanism by which these cells are generated is not completely understood. Here we demonstrate that interferon regulatory factor-8 (IRF8), a transcription factor essential for the development of several myeloid lineages, also regulates basophil and mast cell development.

The transcription factor IRF8 counteracts BCR-ABL to rescue dendritic cell development in chronic myelogenous leukemia.

BCR-ABL tyrosine kinase inhibitors (TKI) have dramatically improved therapy for chronic myelogenous leukemia (CML). However, several problems leading to TKI resistance still impede a complete cure of this disease. IFN regulatory factor-8 (IRF8) is a transcription factor essential for the development and functions of immune cells, including dendritic cells.

Extracts of Larix Leptolepis effectively augments the generation of tumor antigen-specific cytotoxic T lymphocytes via activation of dendritic cells in TLR-2 and TLR-4-dependent manner.

Type-1 immunity plays a crucial role in host defense against various tumors and infectious diseases. Here, we first demonstrated that extract of Larix Leptolepis (ELL), one of the most popular timbers at Hokkaido area in Japan, strongly activated Type-1 immunity. ELL induced production of Type-1 cytokines such as IL-12 and TNF-α from bone marrow-derived dendritic cells (BMDCs) in TLR2- and TLR4-dependent manner and remarkably up-regulated the expression of MHC and co-stimulatory molecules.

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells.

The aryl hydrocarbon receptor (AhR) has been shown to play important roles in the immune system, and contributions of AhR ligands to the differentiation and functions of Th17/Treg cells have recently been established. However, it has not been fully clarified whether AhR plays roles in B cell differentiation and functions. The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly potent AhR agonist, was reported to suppress the production of immunoglobulin M (IgM) in a transformed mouse B cell line.

Toll-like receptor-dependent IL-12 production by dendritic cells is required for activation of natural killer cell-mediated Type-1 immunity induced by Chrysanthemum coronarium L.

Type-1 immunity has an essential role for our host defenses against cancer and outer pathogens such as bacteria and virus. We demonstrated here that the edible plant extract of Chrysanthemum coronarium L. (C.

The extract of Japanese soybean, Kurosengoku activates the production of IL-12 and IFN-γ by DC or NK1.1(+) cells in a TLR4- and TLR2-dependent manner.

During the search for immuno-improving foods, we found that a variety of the Japanese soybean, Glycine max cv. Kurosengoku (Kurosengoku), which activated Type-1 immunity in a Toll-like receptor (TLR)4- and TLR2-dependent manner. Namely, the extract of Kurosengoku first caused production of IL-12 from DC and sequentially induced IFN-γ production by NK1.

Mutation is the Main Driving Force in the Diversification of the Vibrio splendidus Clade.

The Vibrio splendidus clade is the biggest in Vibrionales composed of 11 described species (25). Diversification of these species may have occurred 260 million years ago. The main driving forces of speciation in this clade have never been studied.

Discovery of orally bioavailable cathepsin S inhibitors for the reversal of neuropathic pain.

Cathepsin S inhibitors are well-known to be an attractive target as immunological therapeutic agents. Recently, our gene expression analysis identified that cathepsin S inhibitors could also be effective for neuropathic pain. Herein, we describe the efficacy of selective cathepsin S inhibitors as antihyperalgesics in a model of neuropathic pain in rats after oral administration.

Essential role of Toll-like receptors for dendritic cell and NK1.1(+) cell-dependent activation of type 1 immunity by Lactobacillus pentosus strain S-PT84.

Activation of type 1 immunity plays a critical role in host defense mechanisms against infectious disease and tumor. Lactic acid bacteria, existing in the gastrointestinal tract, are one of the powerful tools to induce a type-1-dominant immunity, which may improve Th2-dependent allergic diseases. In the present work, we found that an oral intake of Lactobacillus pentosus strain, S-PT84 into mice significantly enhanced NK activity of spleen cells in vivo.

Unisized two-dimensional platinum clusters on silicon(111)-7x7 surface observed with scanning tunneling microscope.

Uni-sized platinum clusters (size range of 5-40) on a silicon(111)-7 x 7 surface were prepared by depositing size-selected platinum cluster ions on the silicon surface at the collision energy of 1.5 eV per atom at room temperature. The surface thus prepared was observed by means of a scanning tunneling microscope (STM) at the temperature of 77 K under an ambient pressure less than 5 x 10(-9) Pa.

Lysophospholipase I identified as a ghrelin deacylation enzyme in rat stomach.

Ghrelin, discovered in rat stomach as an endogenous growth hormone secretagogue, is octanoylated at the Ser3 residue. Since this octanoylation is essential for the functions of ghrelin, the enzymes that catalyze acylation for ghrelin biosynthesis and deacylation (deactivation step) must be considered as important regulators. We found that rat stomach homogenate contained ghrelin deacylation activity, and we isolated the active fractions by column chromatography.

Low-energy impact of X-(H2O)n (X = Cl,I) onto solid surface.

We investigated dissociation of X-(H2O)n (X = Cl, I, n = 13-31) by the impact onto a (La0.7Ce0.3)B6(100) surface at a collision energy Ecol of 1-5 eV per water molecule in a tandem time-of-flight mass spectrometer equipped with a translation-energy analyzer.

Association of SH2-B to phosphorylated tyrosine residues in the activation loop of TrkB.

Neurotrophins are essential for the survival and differentiation of neurons in the central and peripheral nervous systems. The binding of neurotrophins to their Trk receptors induces autophosphorylation of tyrosine residues and activation of several signaling components. However, the downstream signaling cascades remain to be fully elucidated.

Distinct usages of phospholipase C gamma and Shc in intracellular signaling stimulated by neurotrophins.

Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), members of the neurotrophin family, bind to and activate TrkA, TrkB and TrkC, respectively, members of the Trk receptor tyrosine kinase family, to exert various effects including promotion of differentiation and survival, and regulation of synaptic plasticity in neuronal cells. Many reports have suggested that different neurotrophins show distinct biological functions, although molecular mechanisms by which neurotrophins exert their different functions remain unclear. In the present study, we found distinct usages of phospholipase Cgamma (PLCgamma) and Shc in intracellular signaling stimulated by neurotrophins.

Brain-derived neurotrophic factor promotes interaction of the Nck2 adaptor protein with the TrkB tyrosine kinase receptor.

Brain-derived neurotrophic factor (BDNF) binds to and activates the TrkB tyrosine kinase receptor to regulate cell differentiation, survival, and neural plasticity in the nervous system. However, the identities of the downstream signaling proteins involved in this process remain unclear. Using a yeast two-hybrid screen with the intracellular domain (ICD-TrkB) of the TrkB BDNF receptor, we identified the Nck2 adaptor protein as a novel interaction partner of the active form of TrkB.

Nerve growth factor enhances neurotransmitter release from PC12 cells by increasing Ca(2+)-responsible secretory vesicles through the activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase.

Neurotrophins play important roles in the differentiation and survival of neurons during development, and in the regulation of synaptic transmission in adult brain. Brief treatment with nerve growth factor (NGF) enhances depolarization and ionomycin-induced dopamine and acetylcholine release from PC12 cells. The enhancing effect appears very quickly and reaches a plateau 10-15 min after application.

Discrimination between phosphotyrosine-mediated signaling properties of conventional and neuronal Shc adapter molecules.

The phosphotyrosine (pTyr) adapter Shc/ShcA is a major connector in various tyrosine kinase signalings following a variety of stimulation such as growth factor/neurotrophin, as well as in those following calcium influx and integrin activation. As in other tissues, Shc has been implicated in neuronal signalings; however, recent evidence suggests that N-Shc/ShcC and Sck/ShcB would take over most of the roles of Shc in mature central neurons, and switching phenomena between Shc and N-Shc expression were observed in several neuronal paradigms. Little is, however, known as to the signal-output differences between Shc and N-Shc.