Details of a Researcher - Fujii, Hideki

Papers - Fujii, Hideki

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Heat Shock Enhances the Expression of the Human T Cell Leukemia Virus Type-I (HTLV-I) Trans-Activator (Tax) Antigen in Human HTLV-I Infected Primary and Cultured T Cells.

Marie Kunihiro, Hideki Fujii, Takuya Miyagi, Yoshiaki Takahashi, Reiko Tanaka, Takuya Fukushima, Aftab A Ansari, Yuetsu Tanaka

Viruses 8 ( 7 ) 2016.07

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

The environmental factors that lead to the reactivation of human T cell leukemia virus type-1 (HTLV-I) in latently infected T cells in vivo remain unknown. It has been previously shown that heat shock (HS) is a potent inducer of HTLV-I viral protein expression in long-term cultured cell lines. However, the precise HTLV-I protein(s) and mechanisms by which HS induces its effect remain ill-defined. We initiated these studies by first monitoring the levels of the trans-activator (Tax) protein induced by exposure of the HTLV-I infected cell line to HS. HS treatment at 43 °C for 30 min for 24 h led to marked increases in the level of Tax antigen expression in all HTLV-I-infected T cell lines tested including a number of HTLV-I-naturally infected T cell lines. HS also increased the expression of functional HTLV-I envelope gp46 antigen, as shown by increased syncytium formation activity. Interestingly, the enhancing effect of HS was partially inhibited by the addition of the heat shock protein 70 (HSP70)-inhibitor pifithlin-μ (PFT). In contrast, the HSP 70-inducer zerumbone (ZER) enhanced Tax expression in the absence of HS. These data suggest that HSP 70 is at least partially involved in HS-mediated stimulation of Tax expression. As expected, HS resulted in enhanced expression of the Tax-inducible host antigens, such as CD83 and OX40. Finally, we confirmed that HS enhanced the levels of Tax and gp46 antigen expression in primary human CD4⁺ T cells isolated from HTLV-I-infected humanized NOD/SCID/γc null (NOG) mice and HTLV-I carriers. In summary, the data presented herein indicate that HS is one of the environmental factors involved in the reactivation of HTLV-I in vivo via enhanced Tax expression, which may favor HTLV-I expansion in vivo.

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A Potential of an Anti-HTLV-I gp46 Neutralizing Monoclonal Antibody (LAT-27) for Passive Immunization against Both Horizontal and Mother-to-Child Vertical Infection with Human T Cell Leukemia Virus Type-I.

Hideki Fujii, Mamoru Shimizu, Takuya Miyagi, Marie Kunihiro, Reiko Tanaka, Yoshiaki Takahashi, Yuetsu Tanaka

Viruses 8 ( 2 ) 2016.02

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

Although the number of human T-cell leukemia virus type-I (HTLV-I)-infected individuals in the world has been estimated at over 10 million, no prophylaxis vaccines against HTLV-I infection are available. In this study, we took a new approach for establishing the basis of protective vaccines against HTLV-I. We show here the potential of a passively administered HTLV-I neutralizing monoclonal antibody of rat origin (LAT-27) that recognizes epitopes consisting of the HTLV-I gp46 amino acids 191-196. LAT-27 completely blocked HTLV-I infection in vitro at a minimum concentration of 5 μg/mL. Neonatal rats born to mother rats pre-infused with LAT-27 were shown to have acquired a large quantity of LAT-27, and these newborns showed complete resistance against intraperitoneal infection with HTLV-I. On the other hand, when humanized immunodeficient mice were pre-infused intravenously with humanized LAT-27 (hu-LAT-27), all the mice completely resisted HTLV-I infection. These results indicate that hu-LAT-27 may have a potential for passive immunization against both horizontal and mother-to-child vertical infection with HTLV-I.

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Osteoprotegerin Regulates Pancreatic β-Cell Homeostasis upon Microbial Invasion.

Yukiko Kuroda, Kenta Maruyama, Hideki Fujii, Isamu Sugawara, Shigeru B H Ko, Hisataka Yasuda, Hidenori Matsui, Koichi Matsuo

PloS one 11 ( 1 ) e0146544 2016

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

Osteoprotegerin (OPG), a decoy receptor for receptor activator of NF-κB ligand (RANKL), antagonizes RANKL's osteoclastogenic function in bone. We previously demonstrated that systemic administration of lipopolysaccharide (LPS) to mice elevates OPG levels and reduces RANKL levels in peripheral blood. Here, we show that mice infected with Salmonella, Staphylococcus, Mycobacteria or influenza virus also show elevated serum OPG levels. We then asked whether OPG upregulation following microbial invasion had an effect outside of bone. To do so, we treated mice with LPS and observed OPG production in pancreas, especially in β-cells of pancreatic islets. Insulin release following LPS administration was enhanced in mice lacking OPG, suggesting that OPG inhibits insulin secretion under acute inflammatory conditions. Consistently, treatment of MIN6 pancreatic β-cells with OPG decreased their insulin secretion following glucose stimulation in the presence of LPS. Finally, our findings suggest that LPS-induced OPG upregulation is mediated in part by activator protein (AP)-1 family transcription factors, particularly Fos proteins. Overall, we report that acute microbial infection elevates serum OPG, which maintains β-cell homeostasis by restricting glucose-stimulated insulin secretion, possibly preventing microbe-induced exhaustion of β-cell secretory capacity.

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Human T-cell leukemia virus type-I Tax induces the expression of CD83 on T cells

Yuetsu Tanaka, Mariko Mizuguchi, Yoshiaki Takahashi, Hideki Fujii, Reiko Tanaka, Takuya Fukushima, Takeaki Tomoyose, Aftab A. Ansari, Masataka Nakamura

RETROVIROLOGY (BIOMED CENTRAL LTD) 12 56 2015.07

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 1742-4690

Background: CD83, a cell surface glycoprotein that is stably expressed on mature dendritic cells, can be transiently induced on other hematopoietic cell lineages upon cell activation. In contrast to the membrane form of CD83, soluble CD83 appears to be immunosuppressive. In an analysis of the phenotype of leukemic CD4(+) T cells from patients with adult T-cell leukemia (ATL), we found that a number of primary CD4(+) T cells became positive for cell surface CD83 after short-term culture, and that most of these CD83(+) CD4(+) T cells were positive for human T-cell leukemia virus type-I (HTLV-I) Tax (Tax1). We hypothesized that Tax1 is involved in the induction of CD83.
Result: We found that CD83 was expressed selectively on Tax1-expressing human CD4(+) T cells in short-term cultured peripheral blood mononuclear cells (PBMCs) isolated from HTLV-I+ donors, including ATL patients and HTLV-I carriers. HTLV-I-infected T cell lines expressing Tax1 also expressed cell surface CD83 and released soluble CD83. CD83 can be expressed in the JPX-9 cell line by cadmium-mediated Tax1 induction and in Jurkat cells or PBMCs by Tax1 introduction via infection with a recombinant adenovirus carrying the Tax1 gene. The CD83 promoter was activated by Tax1 in an NF-kappa B-dependent manner. Based on a previous report showing soluble CD83-mediated prostaglandin E2 (PGE2) production from human monocytes in vitro, we tested if PGE2 affected HTLV-I propagation, and found that PGE2 strongly stimulated expression of Tax1 and viral structural molecules.
Conclusions: Our results suggest that HTLV-I induces CD83 expression on T cells via Tax1 -mediated NF-kappa B activation, which may promote HTLV-I infection in vivo.

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The neutralizing function of the anti-HTLV-1 antibody is essential in preventing in vivo transmission of HTLV-1 to human T cells in NOD-SCID/γcnull (NOG) mice.

Mineki Saito, Reiko Tanaka, Hideki Fujii, Akira Kodama, Yoshiaki Takahashi, Toshio Matsuzaki, Hiroshi Takashima, Yuetsu Tanaka

Retrovirology 11 74 - 74 2014.08

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) causes both neoplastic and inflammatory diseases, including adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Because these life-threatening and disabling diseases are not yet curable, it is important to prevent new HTLV-1 infections. FINDINGS: In this study, we have established a simple humanized mouse model of HTLV-1 infection for evaluating prophylactic and therapeutic interventions. In this model, HTLV-1-negative normal human peripheral blood mononuclear cells (PBMCs) are transplanted directly into the spleens of severely immunodeficient NOD-SCID/γcnull (NOG) mice, together with mitomycin-treated HTLV-1-producing T cells. Using this model, we tested the efficacy of monoclonal antibodies (mAbs) specific to HTLV-1 as well as human IgG isolated from HAM/TSP patients (HAM-IgG) in preventing HTLV-1-infection. One hour before and 24 h after transplantation of the human cells, each antibody sample was inoculated intraperitoneally. On day 14, human PBMCs isolated from the mouse spleens were tested for HTLV-1 infection. Whereas fresh CD4-positive and CD8-positive T cells isolated from untreated mice or mice treated with isotype control mAb, HTLV-1 non-neutralizing mAbs to envelope gp46, gag p19, and normal human IgG were all infected with HTLV-1; the mice treated with either HTLV-1 neutralizing anti-gp46 mAb or HAM-IgG did not become infected. CONCLUSIONS: Our data indicate that the neutralizing function of the antibody, but not the antigen specificity, is essential for preventing the in vivo transmission of HTLV-1. The present animal model will also be useful for the in vivo evaluation of the efficacy of candidate molecules to be used as prophylactic and therapeutic intervention against HTLV-1 infection.

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Elimination of Human T Cell Leukemia Virus Type-1-Infected Cells by Neutralizing and Antibody-Dependent Cellular Cytotoxicity-Inducing Antibodies Against Human T Cell Leukemia Virus Type-1 Envelope gp46

Yuetsu Tanaka, Yoshiaki Takahashi, Reiko Tanaka, Akira Kodama, Hideki Fujii, Atsuhiko Hasegawa, Mari Kannagi, Aftab A. Ansari, Mineki Saito

AIDS RESEARCH AND HUMAN RETROVIRUSES (MARY ANN LIEBERT, INC) 30 ( 6 ) 542 - 552 2014.06

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0889-2229

Human T cell leukemia virus type-1 (HTLV-1) is prevalent worldwide with foci of high prevalence. However, to date no effective vaccine or drug against HTLV-1 infection has been developed. In efforts to define the role of antibodies in the control of HTLV-1 infection, we capitalized on the use of our previously defined anti-gp46 neutralizing monoclonal antibody (mAb) (clone LAT-27) and high titers of human anti-HTLV-1 IgG purified from HAM/TSP patients (HAM-IgG). LAT-27 and HAM-IgG completely blocked syncytium formation and T cell immortalization mediated by HTLV-1 in vitro. The addition of these antibodies to cultures of CD8(+) T cell-depleted peripheral blood mononuclear cells (PBMCs) from HAM/TSP patients at the initiation of culture not only decreased the numbers of Tax-expressing cells and the production of HTLV-1 p24 but also inhibited the spontaneous immortalization of T cells. Coculture of in vitro-HTLV-1-immortalized T cell lines with autologous PBMCs in the presence of LAT-27 or HAM-IgG, but not an F(ab) 2 fragment of LAT-27 or non-neutralizing anti-gp46 mAbs, resulted in depletion of HTLV-1-infected cells. A 24-h Cr-51 release assay showed the presence of significant antibody-dependent cellular cytotoxicity (ADCC) activity in LAT-27 and HAM-IgG, but not F(ab) 2 of LAT-27, resulting in the depletion of HTLV-1-infected T cells by autologous PBMCs. The depletion of natural killer (NK) cells from the effector PBMCs reduced this ADCC activity. Altogether, the present data demonstrate that the neutralizing and ADCC-inducing activities of anti-HTLV-1 antibodies are capable of reducing infection and eliminating HTLV-1-infected cells in the presence of autologous PBMCs.

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Phagocytic cells contribute to the antibody-mediated elimination of pulmonary-infected SARS coronavirus.

Fumihiko Yasui, Michinori Kohara, Masahiro Kitabatake, Tetsu Nishiwaki, Hideki Fujii, Chise Tateno, Misako Yoneda, Kouichi Morita, Kouji Matsushima, Shigeo Koyasu, Chieko Kai

Virology (ACADEMIC PRESS INC ELSEVIER SCIENCE BV) 454-455: 157 - 68 2014.03

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

While the 2002-2003 outbreak of severe acute respiratory syndrome (SARS) resulted in 774 deaths, patients who were affected with mild pulmonary symptoms successfully recovered. The objective of the present work was to identify, using SARS coronavirus (SARS-CoV) mouse infection models, immune factors responsible for clearing of the virus. The elimination of pulmonary SARS-CoV infection required the activation of B cells by CD4(+) T cells. Furthermore, passive immunization (post-infection) with homologous (murine) anti-SARS-CoV antiserum showed greater elimination efficacy against SARS-CoV than that with heterologous (rabbit) antiserum, despite the use of equivalent titers of neutralizing antibodies. This distinction was mediated by mouse phagocytic cells (monocyte-derived infiltrating macrophages and partially alveolar macrophages, but not neutrophils), as demonstrated both by adoptive transfer from donors and by immunological depletion of selected cell types. These results indicate that the cooperation of anti-SARS-CoV antibodies and phagocytic cells plays an important role in the elimination of SARS-CoV.

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Influenza A whole virion vaccine induces a rapid reduction of peripheral blood leukocytes via interferon-α-dependent apoptosis.

Manabu Ato, Yoshimasa Takahashi, Hideki Fujii, Shu-ichi Hashimoto, Tomohiro Kaji, Shigeyuki Itamura, Yoshinobu Horiuchi, Yoshichika Arakawa, Masato Tashiro, Toshitada Takemori

Vaccine 31 ( 17 ) 2184 - 90 2013.04

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

Infection with single strand RNA (ssRNA) viruses, such as influenza A virus, is known to induce protective acquired immune responses, including the production of neutralizing antibodies. Vaccination also causes a reduction in the number of peripheral blood leukocytes (PBL) shortly after inoculation, a result which may have undesirable adverse effects. The cellular mechanisms for this response have not been elucidated so far. Here we report that formalin-inactivated influenza A whole virus vaccine (whole virion) induces a significant decrease in PBL in mice 5-16 h after administration, whereas an ether-split vaccine (HA split) made from the same influenza virus strain does not induce a similar loss of PBL. Concordant with this reduction in the number of PBL, a rapidly induced and massive production of interferon (IFN)-α is observed when mice are injected with whole virion, but not with HA split vaccines. The role of Toll-like receptors (TLR), which are involved in signal transduction of influenza virus, and the subsequent induction of IFNα were confirmed using mice lacking TLR7, MyD-88, or IFNα/β receptor. We further demonstrated that the observed PBL loss is caused by apoptosis in an IFNα-dependent manner, and not by leukocyte redistribution due to chemokine signaling failure. These findings indicate that RNA-encapsulated whole virion vaccines can rapidly induce a loss of leukocytes from peripheral blood by apoptosis, which may modulate the subsequent immune response.

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Modulation of murine macrophage TLR7/8-mediated cytokine expression by mesenchymal stem cell-conditioned medium.

Takahiro Asami, Makoto Ishii, Hideki Fujii, Ho Namkoong, Sadatomo Tasaka, Kenichi Matsushita, Ken Ishii, Kazuma Yagi, Hiroshi Fujiwara, Yohei Funatsu, Naoki Hasegawa, Tomoko Betsuyaku

Mediators of inflammation 2013 264260 - 264260 2013

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

Increasing evidence suggests that mesenchymal stem cells (MSCs) play anti-inflammatory roles during innate immune responses. However, little is known about the effect of MSCs or their secretions on the ligand response of Toll-like receptor (TLR) 7 and TLR8, receptors that recognize viral single-stranded RNA (ssRNA). Macrophages play a critical role in the innate immune response to ssRNA virus infection; therefore, we investigated the effect of MSC-conditioned medium on cytokine expression in macrophages following stimulation with TLR7/8 ligands. After stimulation with TLR7/8 ligand, bone marrow-derived macrophages cultured with MSCs or in MSC-conditioned medium expressed lower levels of tumor necrosis factor (TNF) α and interleukin (IL) 6 and higher levels of IL-10 compared to macrophages cultured without MSCs or in control medium, respectively. The modulations of cytokine expression were associated with prostaglandin E2 (PGE2) secreted by the MSCs. PGE2 enhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor- κ B (NF- κ B) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF- κ B signaling contributed to the low production of TNF- α . Collectively, these results indicate that MSCs and MSC-conditioned medium modulate the cytokine expression profile in macrophages following TLR7/8-mediated stimulation, which suggests that MSCs play an immunomodulatory role during ssRNA virus infection.

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Cutting edge: mTORC1 in intestinal CD11c+ CD11b+ dendritic cells regulates intestinal homeostasis by promoting IL-10 production.

Masashi Ohtani, Takayuki Hoshii, Hideki Fujii, Shigeo Koyasu, Atsushi Hirao, Satoshi Matsuda

Journal of immunology (Baltimore, Md. : 1950) 188 ( 10 ) 4736 - 40 2012.05

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

The mammalian target of rapamycin (mTOR) controls cell growth and survival through two distinct complexes called mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Although several reports have suggested the involvement of mTORC1 in development and function of dendritic cells (DCs), its physiological roles remain obscure. We therefore established mTORC1 signal-deficient mice lacking Raptor, an essential component of mTORC1 signal, specifically in DC lineage (referred to here as Raptor(DC-/-)). Raptor(DC-/-) mice exhibited cell expansion in specific subsets of DCs such as splenic CD8(+) DCs and intestinal CD11c(+)CD11b(+) DCs. We also found that impaired mTORC1 signal resulted in the suppression of IL-10 production along with enhanced CD86 expression in intestinal CD11c(+)CD11b(+) DCs and that Raptor(DC-/-) mice were highly susceptible to dextran sodium sulfate-induced colitis. Our results uncover mTORC1-mediated anti-inflammatory programs in intestinal CD11c(+)CD11b(+) DCs to limit the intestinal inflammation.

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Desmoglein 3-specific CD4(+) T cells induce pemphigus vulgaris and interface dermatitis in mice.

Hayato Takahashi, Michiyoshi Kouno, Keisuke Nagao, Naoko Wada, Tsuyoshi Hata, Shuhei Nishimoto, Yoichiro Iwakura, Akihiko Yoshimura, Taketo Yamada, Masataka Kuwana, Hideki Fujii, Shigeo Koyasu, Masayuki Amagai

Journal of Clinical Investigation (AMER SOC CLINICAL INVESTIGATION INC) 121 ( 9 ) 3677 - 3688 2011.08

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0021-9738

Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4(+) T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3(-/-) mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell-mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-γ- and TCR avidity-dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell-mediated skin diseases.

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HIV-1 Nef impairs multiple T-cell functions in antigen-specific immune response in mice.

Hideki Fujii, Manabu Ato, Yoshimasa Takahashi, Kaori Otake, Shu-ichi Hashimoto, Tomohiro Kaji, Yasuko Tsunetsugu-Yokota, Mikako Fujita, Akio Adachi, Toshinori Nakayama, Masaru Taniguchi, Shigeo Koyasu, Toshitada Takemori

International Immunology (OXFORD UNIV PRESS) 23 ( 7 ) 433 - 441 2011.06

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0953-8178

The viral protein Nef is a key element for the progression of HIV disease. Previous in vitro studies suggested that Nef expression in T-cell lines enhanced TCR signaling pathways upon stimulation with TCR cross-linking, leading to the proposal that Nef lowers the threshold of T-cell activation, thus increasing susceptibility to viral replication in immune response. Likewise, the in vivo effects of Nef transgenic mouse models supported T-cell hyperresponse by Nef. However, the interpretation is complicated by Nef expression early in the development of T cells in these animal models. Here, we analyzed the consequence of Nef expression in ovalbumin-specific/CD4(+) peripheral T cells by using a novel mouse model and demonstrate that Nef inhibits antigen-specific T-cell proliferation and multiple functions required for immune response in vivo, which includes T-cell helper activity for the primary and memory B-cell response. However, Nef does not completely abrogate T-cell activity, as defined by low levels of cytokine production, which may afford the virus a replicative advantage. These results support a model, in which Nef expression does not cause T-cell hyperresponse in immune reaction, but instead reduces the T-cell activity, that may contribute to a low level of virus spread without viral cytopathic effects.

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Diet-induced adipose tissue inflammation and liver steatosis are prevented by DPP-4 inhibition in diabetic mice.

Jun Shirakawa, Hideki Fujii, Kei Ohnuma, Koichiro Sato, Yuzuru Ito, Mitsuyo Kaji, Eri Sakamoto, Megumi Koganei, Hajime Sasaki, Yoji Nagashima, Kikuko Amo, Kazutaka Aoki, Chikao Morimoto, Eiji Takeda, Yasuo Terauchi

Diabetes 60 ( 4 ) 1246 - 57 2011.04

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted

OBJECTIVE: Diet composition alters the metabolic states of adipocytes and hepatocytes in diabetes. The effects of dipeptidyl peptidase-4 (DPP-4) inhibition on adipose tissue inflammation and fatty liver have been obscure. We investigated the extrapancreatic effects of DPP-4 inhibition on visceral fat and the liver. RESEARCH DESIGN AND METHODS: We investigated diet-induced metabolic changes in β-cell-specific glucokinase haploinsufficient (Gck(+/-)) diabetic mice. We challenged animals with a diet containing a combination of sucrose and oleic acid (SO) or sucrose and linoleic acid (SL). Next, we assessed the effects of a DPP-4 inhibitor, des-fluoro-sitagliptin, on adipose tissue inflammation and hepatic steatosis. RESULTS: The epididymal fat weight and serum leptin level were significantly higher in Gck(+/-) mice fed SL than in mice fed SO, although no significant differences in body weight or adipocyte size were noted. Compared with SO, SL increased the numbers of CD11c(+) M1 macrophages and CD8(+) T-cells in visceral adipose tissue and the expression of E-selectin, P-selectin, and plasminogen activator inhibitor-1 (PAI-1). DPP-4 inhibition significantly prevented adipose tissue infiltration by CD8(+) T-cells and M1 macrophages and decreased the expression of PAI-1. The production of cytokines by activated T-cells was not affected by DPP-4 inhibition. Furthermore, DPP-4 inhibition prevented fatty liver in both wild-type and Gck(+/-) mice. DPP-4 inhibition also decreased the expressions of sterol regulatory element-binding protein-1c, stearoyl-CoA desaturase-1, and fatty acid synthase, and increased the expression of peroxisome proliferator-activated receptor-α in the liver. CONCLUSIONS: Our findings indicated that DPP-4 inhibition has extrapancreatic protective effects against diet-induced adipose tissue inflammation and hepatic steatosis.

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Langerhans cell antigen capture through tight junctions confers preemptive immunity in experimental staphylococcal scalded skin syndrome

Takeshi Ouchi, Akiharu Kubo, Mariko Yokouchi, Takeya Adachi, Tetsuro Kobayashi, Daniela Y. Kitashima, Hideki Fujii, Björn E. Clausen, Shigeo Koyasu, Masayuki Amagai, Keisuke Nagao

The Journal of Experimental Medicine (Rockefeller University Press) 208 ( 13 ) 2607 - 2613 2011

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0022-1007

Epidermal Langerhans cells (LCs) extend dendrites through tight junctions (TJs) to survey the skin surface, but their immunological contribution in vivo remains elusive. We show that LCs were essential for inducing IgG(1) responses to patch-immunized ovalbumin in mice that lacked skin dendritic cell subsets. The significance of LC-induced humoral responses was demonstrated in a mouse model of staphylococcal scalded skin syndrome (SSSS), a severe blistering disease in which the desmosomal protein Dsg1 (desmoglein1) is cleaved by Staphylococcus aureus-derived exfoliative toxin (ET). Importantly, ET did not penetrate TJs, and patch immunization did not alter epidermal integrity. Nevertheless, neutralizing anti-ET IgG(1) was induced after patch immunization and abolished upon LC depletion, indicating that antigen capture through TJs by LCs induced humoral immunity. Strikingly, the ET-patched mice were protected from developing SSSS after intraperitoneal ET challenge, whereas LC-depleted mice were susceptible to SSSS, demonstrating a vital role for LC-induced IgG(1) in systemic defense against circulating toxin in vivo. Therefore, LCs elicit humoral immunity to antigens that have not yet violated the epidermal barrier, providing preemptive immunity against potentially pathogenic skin microbes. Targeting this immunological process confers protection with minimal invasiveness and should have a marked impact on future strategies for development of percutaneous vaccines.

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Thymoproteasome Shapes Immunocompetent Repertoire of CD8(+) T Cells

Takeshi Nitta, Shigeo Murata, Katsuhiro Sasaki, Hideki Fujii, Adiratna Mat Ripen, Naozumi Ishimaru, Shigeo Koyasu, Keiji Tanaka, Yousuke Takahama

IMMUNITY (CELL PRESS) 32 ( 1 ) 29 - 40 2010.01

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 1074-7613

How self-peptides displayed in the thymus contribute to the development of immunocompetent and self-protective T cells is largely unknown. In contrast, the role of thymic self-peptides in eliminating self-reactive T cells and thereby preventing autoimmunity is well established. A type of proteasome, termed thymoproteasome, is specifically expressed by thymic cortical epithelial cells (cTECs) and is required for the generation of optimal cellularity of CD8(+) T cells. Here, we show that cTECs displayed thymoproteasome-specific peptide-MHC class I complexes essential for the positive selection of major and diverse repertoire of MHC class I-restricted T cells. CD8(+) T cells generated in the absence of thymoproteasomes displayed a markedly altered T cell receptor repertoire that was defective in both allogeneic and antiviral responses. These results demonstrate that thymoproteasome-dependent self-peptide production is required for the development of an immunocompetent repertoire of CD8(+) T cells.

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Innate production of T(H)2 cytokines by adipose tissue-associated c-Kit(+)Sca-1(+) lymphoid cells.

Kazuyo Moro, Taketo Yamada, Masanobu Tanabe, Tsutomu Takeuchi, Tomokatsu Ikawa, Hiroshi Kawamoto, Jun-ichi Furusawa, Masashi Ohtani, Hideki Fujii, Shigeo Koyasu

Nature (NATURE PUBLISHING GROUP) 463 ( 7280 ) 540 - 544 2009.12

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0028-0836

Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus-infected cells and produce various cytokines(1,2). Here we report a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but do express c-Kit, Sca-1 (also known as Ly6a), IL7R and IL33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue 'FALC' (fat-associated lymphoid cluster). FALC Lin(-)c-Kit(+)Sca-1(+) cells are distinct from lymphoid progenitors(3) and lymphoid tissue inducer cells(4). These cells proliferate in response to IL2 and produce large amounts of T(H)2 cytokines such as IL5, IL6 and IL13. IL5 and IL6 regulate B-cell antibody production and self-renewal of B1 cells(5-7). Indeed, FALC Lin(-)c-Kit(+)Sca-1(+) cells support the self-renewal of B1 cells and enhance IgA production. IL5 and IL13 mediate allergic inflammation and protection against helminth infection(8,9). After helminth infection and in response to IL33, FALC Lin(-)c-Kit(+)Sca-1(+) cells produce large amounts of IL13, which leads to goblet cell hyperplasia-a critical step for helminth expulsion. In mice devoid of FALC Lin(-)c-Kit(+)Sca-1(+) cells, such goblet cell hyperplasia was not induced. Thus, FALC Lin(-)c-Kit(+)Sca-1(+) cells are T(H)2-type innate lymphocytes, and we propose that these cells be called 'natural helper cells'.

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Critical roles of NK and CD8(+) T cells in central nervous system Listeriosis.

Toshiyuki Hayashi, Shigenori Nagai, Hideki Fujii, Yukiko Baba, Eiji Ikeda, Takeshi Kawase, Shigeo Koyasu

Journal of Immunology (AMER ASSOC IMMUNOLOGISTS) 182 ( 10 ) 6360 - 6368 2009.05

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0022-1767

Listeria monocytogenes (LM) causes a life-threatening infectious disease affecting the brain of humans and domestic animals. Unfortunately, no adequate murine models for CNS listeriosis exist. Using intraparenchymal injection, we have established a new murine model for CNS listeriosis. Injection of a small volume of bacterial suspension limits the bacteria to the brain parenchyma with no leakage into the ventricular system. This new method enabled us to investigate the progression of and recovery from listerial brain infection, revealing roles for both innate and adaptive immune cells in CNS listeriosis. In the early phase of CNS listeriosis, INK cell-derived IFN-gamma is a critical cytokine in the limitation of bacterial growth by the host defense. During the later phase, CD8(+) but not CD4(+) T cells play a critical role and LM-specific CD8(+) T cells kill LM-infected microglia. Thus, innate and adaptive immune responses combine to successfully eliminate bacteria from the brain. The Journal of Immunology, 2009, 182: 6360-6368.

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PI3K is a negative regulator of IgE production.

Tomomitsu Doi, Kunie Obayashi, Takashi Kadowaki, Hideki Fujii, Shigeo Koyasu

International Immunology (OXFORD UNIV PRESS) 20 ( 4 ) 499 - 508 2008.02

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0953-8178

The production of IgE, a main player in allergic disorders such as asthma and atopic dermatitis, is strictly regulated and the serum concentrations of IgE are normally kept at a much lower level than other isotypes. We found that mice deficient for the p85α regulatory subunit of class IA phosphoinositide 3-kinase (PI3K) produced increasing amounts of serum IgE. Purified p85α(-/-) B cells produced more IgE than wild-type B cells in vitro in response to anti-CD40 mAb and IL-4. PI3K inhibitors wortmannin and IC87114 enhanced IgE production by wild-type B cells stimulated with anti-CD40 mAb and IL-4. Under the same condition, antigen receptor cross-linking induced the expression of inhibitor of differentiation-2 and suppressed the expression of activation-induced cytidine deaminase and class switch recombination (CSR) in a PI3K-dependent manner. IgE production was also suppressed in a concentrated cell culture condition, which was completely reversed by PI3K inhibition. The selective suppression of IgE production by PI3K was also observed at a protein level after CSR. Our results indicate that PI3K negatively regulates IgE production at both CSR and protein levels.

Access to Document (DOI)

Effect of prostatic neuropeptides on invasion and migration of PC-3 prostate cancer cells.

O Nagakawa, M Ogasawara, H Fujii, K Murakami, J Murata, H Fuse, I Saiki

Cancer letters 133 ( 1 ) 27 - 33 1998.11

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0304-3835

We investigated the effect of various neuropeptides present in the prostate, including calcitonin gene-related peptide (CGRP), gastrin-releasing peptide (GRP), substance P (SP), neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), calcitonin (CT), leucine-enkephalin (L-ENK), glucagon and parathyroid hormone-related protein (PTH-rP), on the invasion of PC-3 prostate cancer cells through a reconstituted basement membrane (Matrigel) using a Transwell cell culture chamber assay. Both CGRP and GRP increased the invasive capacity of tumor cells, whereas SP inhibited it. On the other hand, VIP, CT, L-ENK, NPY, glucagon and PTH-rP had no significant effect. Both CGRP and GRP also increased the haptotactic migration of tumor cells to fibronectin, but SP inhibited it. These three neuropeptides had no effect on either adhesion to fibronectin and laminin or on the gelatinolytic activities of MMP-9 in gelatin zymography, nor did they affect the growth of tumor cells at concentrations used in this study. These results indicate that both GRP and CGRP increased the invasive potential of PC-3 cells probably through enhancement of cell motility, while SP inhibited the invasiveness through suppression of motile response.

Anti-metastatic and immunomodulating properties of the water extract from Celosia argentea seeds.

Y Hayakawa, H Fujii, K Hase, Y Ohnishi, R Sakukawa, S Kadota, T Namba, I Saiki

Biological & pharmaceutical bulletin 21 ( 11 ) 1154 - 9 1998.11

Research paper (scientific journal), Joint Work, Lead author, Last author, Corresponding author, Accepted, ISSN 0918-6158

We have investigated the anti-metastatic effect of Celosia argentea seed extracts (CAE), which have traditionally been used as a therapeutic drug for eye and hepatic diseases in China and Japan. Intraperitoneal (i.p.) administration of CAE for 7 d before tumor inoculation significantly inhibited liver metastasis caused by intraportal injection of colon 26-L5 carcinoma cells in a dose-dependent manner. CAE also showed concentration dependent mitogenic activity on BALB/c whole splenocytes, whereas incubation of the non-adherent fraction of splenocytes with CAE did not induce this activity. CAE has the ability to induce interleukin (IL)-12 production from macrophages in vitro. Following i.p. administration of CAE the maximal levels of IL-12 and interferon (IFN)-gamma production in serum were achieved at 2-3 and 6 h, respectively. Experiments using macrophage- or NK cell-deficient mice revealed that CAE-induced IL-12 in serum was not mediated by macrophages and that IFN-gamma production was mainly dependent on natural killer (NK) cells. Since CAE was inactive when the contributions of macrophages were removed in our system, its inhibitory mechanism is likely to be mainly associated with the activation of macrophages to an anti-metastatic state rather than NK cells. CAE administration resulted in increased production of IL-2, IFN-gamma and decreased production of a Th2 cytokine (IL-4) from splenocytes stimulated by PMA and A23187. Thus, the anti-metastatic effect by CAE is based on its immunomodulating properties including induction of cytokines such as IL-12, IL-2 and IFN-gamma leading to a Th1 dominant immune state and activating macrophages to the tumoricidal state. This may provide a basis for the inhibition of cancer metastasis.

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