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Dive into the research topics where Wataru Fujii is active.

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Featured researches published by Wataru Fujii.


Journal of Immunology | 2013

Myeloid-Derived Suppressor Cells Play Crucial Roles in the Regulation of Mouse Collagen-Induced Arthritis

Wataru Fujii; Eishi Ashihara; Hideyo Hirai; Hidetake Nagahara; Naoko Kajitani; Kazuki Fujioka; Ken Murakami; Takahiro Seno; Aihiro Yamamoto; Hidetaka Ishino; Masataka Kohno; Taira Maekawa; Yutaka Kawahito

Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. The role of MDSCs in autoimmune diseases remains controversial, and little is known about the function of MDSCs in autoimmune arthritis. In this study, we clarify that MDSCs play crucial roles in the regulation of proinflammatory immune response in a collagen-induced arthritis (CIA) mouse model. MDSCs accumulated in the spleens of mice with CIA when arthritis severity peaked. These MDSCs inhibited the proliferation of CD4+ T cells and their differentiation into Th17 cells in vitro. Moreover, MDSCs inhibited the production of IFN-γ, IL-2, TNF-α, and IL-6 by CD4+ T cells in vitro, whereas they promoted the production of IL-10. Adoptive transfer of MDSCs reduced the severity of CIA in vivo, which was accompanied by a decrease in the number of CD4+ T cells and Th17 cells in the draining lymph nodes. However, depletion of MDSCs abrogated the spontaneous improvement of CIA. In conclusion, MDSCs in CIA suppress the progression of CIA by inhibiting the proinflammatory immune response of CD4+ T cells. These observations suggest that MDSCs play crucial roles in the regulation of autoimmune arthritis, which could be exploited in new cell-based therapies for human rheumatoid arthritis.


Modern Rheumatology | 2012

The rapid efficacy of abatacept in a patient with rheumatoid vasculitis

Wataru Fujii; Masataka Kohno; Hidetaka Ishino; Amane Nakabayashi; Kazuki Fujioka; Takashi Kida; Hidetake Nagahara; Ken Murakami; Kaoru Nakamura; Takahiro Seno; Aihiro Yamamoto; Yutaka Kawahito

We report a case of rheumatoid vasculitis (RV) that responded well to abatacept, a cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-immunoglobulin fusion protein. A 38-year-old woman developed RV despite treatment with methotrexate and tumor necrosis factor (TNF) inhibitors. The effects of steroid therapy, immunoabsorption plasmapheresis, and interleukin-6 inhibitor were insufficient, however, administration of abatacept rapidly improved her clinical symptoms with almost normalization of the immunological findings. This is the first published case report of the successful treatment of RV with abatacept.


PLOS ONE | 2014

Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

Ken Murakami; Masataka Kohno; Masatoshi Kadoya; Hidetake Nagahara; Wataru Fujii; Takahiro Seno; Aihiro Yamamoto; Ryo Oda; Hiroyoshi Fujiwara; Toshikazu Kubo; Satoshi Morita; Hiroshi Nakada; Timothy Hla; Yutaka Kawahito

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein–coupled receptors (S1P1–5). Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO)) mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT) mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF) collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF) levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1) or transforming growth factor β1 (TGF-β1) levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.


Arthritis & Rheumatism | 2015

Monocarboxylate Transporter 4, Associated With the Acidification of Synovial Fluid, Is a Novel Therapeutic Target for Inflammatory Arthritis

Wataru Fujii; Yutaka Kawahito; Hidetake Nagahara; Yuji Kukida; Takahiro Seno; Aihiro Yamamoto; Masataka Kohno; Ryo Oda; Daigo Taniguchi; Hiroyoshi Fujiwara; Akika Ejima; Tsunao Kishida; Osam Mazda; Eishi Ashihara

Synovial fluid pH is decreased in patients with rheumatoid arthritis (RA); however, the underlying mechanisms are unclear. We undertook this study to examine the mechanism by which synovial fluid pH is regulated and to explore the possibility of a therapeutic strategy by manipulating this mechanism.


Biochemical and Biophysical Research Communications | 2015

Inhibition of osteoclastogenesis by osteoblast-like cells genetically engineered to produce interleukin-10

Kazuki Fujioka; Tsunao Kishida; Akika Ejima; Kenta Yamamoto; Wataru Fujii; Ken Murakami; Takahiro Seno; Aihiro Yamamoto; Masataka Kohno; Ryo Oda; Toshiro Yamamoto; Hiroyoshi Fujiwara; Yutaka Kawahito; Osam Mazda

Bone destruction at inflamed joints is an important complication associated with rheumatoid arthritis (RA). Interleukin-10 (IL-10) may suppress not only inflammation but also induction of osteoclasts that play key roles in the bone destruction. If IL-10-producing osteoblast-like cells are induced from patient somatic cells and transplanted back into the destructive bone lesion, such therapy may promote bone remodeling by the cooperative effects of IL-10 and osteoblasts. We transduced mouse fibroblasts with genes for IL-10 and Runx2 that is a crucial transcription factor for osteoblast differentiation. The IL-10-producing induced osteoblast-like cells (IL-10-iOBs) strongly expressed osteoblast-specific genes and massively produced bone matrix that were mineralized by calcium phosphate in vitro and in vivo. Culture supernatant of IL-10-iOBs significantly suppressed induction of osteoclast from RANKL-stimulated Raw264.7 cells as well as LPS-induced production of inflammatory cytokine by macrophages. The IL-10-iOBs may be applicable to novel cell-based therapy against bone destruction associated with RA.


BioScience Trends | 2016

Allograft inflammatory factor-1 in the pathogenesis of bleomycin-induced acute lung injury

Hidetake Nagahara; Aihiro Yamamoto; Takahiro Seno; Hiroshi Obayashi; Takashi Kida; Amane Nakabayashi; Yuji Kukida; Kazuki Fujioka; Wataru Fujii; Ken Murakami; Masataka Kohno; Yutaka Kawahito

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries of rats with an ectopic cardiac allograft. Some studies have shown that expression of AIF-1 increased in a mouse model of trinitrobenzene sulfonic acid-induced acute colitis and in acute cellular rejection of human cardiac allografts. These results suggest that AIF-1 is related to acute inflammation. The current study used bleomycin-induced acute lung injury to analyze the expression of AIF-1 and to examine its function in acute lung injury. Results showed that AIF-1 was significantly expressed in lung macrophages and increased in bronchoalveolar lavage fluid from mice with bleomycin-induced acute lung injury in comparison to control mice. Recombinant AIF-1 increased the production of IL-6 and TNF-α from RAW264.7 (a mouse macrophage cell line) and primary lung fibroblasts, and it also increased the production of KC (CXCL1) from lung fibroblasts. These results suggest that AIF-1 plays an important role in the mechanism underlying acute lung injury.


American Journal of Physiology-lung Cellular and Molecular Physiology | 2018

Roles of high-mobility group box 1 and thrombin in murine pulmonary fibrosis and the therapeutic potential of thrombomodulin

Takashi Kida; Takahiro Seno; Hidetake Nagahara; Takuya Inoue; Amane Nakabayashi; Yuji Kukida; Kazuki Fujioka; Wataru Fujii; Makoto Wada; Masataka Kohno; Yutaka Kawahito

Cross talk between inflammation and coagulation plays important roles in acute or subacute progressive pulmonary fibrosis characterized by diffuse alveolar damage. Thrombomodulin is a physiological inhibitor of high-mobility group box 1 (HMGB1), and thrombin and may be effective for this condition. This study investigated the roles of HMGB1 and thrombin in the pathophysiology of bleomycin-induced pulmonary fibrosis and the efficacy of recombinant human soluble thrombomodulin (rhTM). Pulmonary fibrosis was induced in wild-type C57BL/6 mice by intratracheal instillation of bleomycin. We first assessed HMGB1, thrombin, transforming growth factor (TGF)-β1, and α-smooth muscle actin (SMA) levels in bronchoalveolar lavage fluid and lung tissue sections over time. Expression of HMGB1 and thrombin was elevated before that of TGF-β1 and α-SMA and remained high during the fibrotic phase after bleomycin instillation. We next examined whether in vitro stimulation with HMGB1 and thrombin induced expression of TGF-β1 and α-SMA in cultured alveolar macrophages and lung fibroblasts, respectively, by performing quantitative PCR, enzyme-linked immunosorbent assay, Western blot, and immunofluorescence analyses. HMGB1 and thrombin stimulation induced TGF-β1 production by alveolar macrophages, and thrombin stimulation also induced α-SMA expression in lung fibroblasts. Finally, we evaluated the effect of rhTM on bleomycin-induced pulmonary fibrosis. Compared with the vehicle control, both early and late-phase administration of rhTM suppressed the fibrotic process. Our results suggest that HMGB1 and thrombin were involved in the pathophysiology of pulmonary fibrosis via production of profibrotic proteins and that rhTM attenuated bleomycin-induced pulmonary fibrosis. rhTM may be a therapeutic option for acute or subacute pulmonary fibrosis.


Annals of the Rheumatic Diseases | 2013

THU0112 Myeloid-Derived Suppressor Cells have Regulatory Roles in Mouse Collagen-Induced Arthritis

Wataru Fujii; Eishi Ashihara; Hideyo Hirai; Hidetake Nagahara; Kazuki Fujioka; Ken Murakami; Takahiro Seno; Aihiro Yamamoto; Hidetaka Ishino; Masataka Kohno; Taira Maekawa; Yutaka Kawahito

Background Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. MDSCs are characterized by the co-expression of the myeloid differentiation antigens Gr-1 and CD11b in mice (1). MDSCs in cancer have been studied in detail and are known to play roles in tumor associated immune suppression. However, the roles of MDSCs in autoimmune disease remain controversial and little is known about MDSCs in autoimmune arthritis. Objectives We investigate the roles of MDSCs in autoimmune arthritis using collagen-induced arthritis (CIA) mouse models. Methods We determined the number of Gr-1+ CD11b+ MDSCs in the spleens of CIA mice by flow cytometry. Next, we isolated MDSCs from CIA mice by magnetic cell sorting and cultured with CD4+ T cells to analyze the functions of MDSCs. We investigated the proliferation of CD4+ T cells by CFSE dye dilution assay and estimated cytokine levels produced by CD4+ T cells using ELISA. Furthermore, we investigated CD4+ T cell differentiation into Th17 cells by flow cytometry. Finally, we performed adoptive transfer of MDSCs into CIA mice and investigated the severity of arthritis. Results MDSCs significantly accumulated in the spleens of mice with CIA when arthritis severity peaked. These MDSCs inhibited CD4+ T cell proliferation and differentiation into Th17 cells. Moreover, MDSCs inhibited the production of IFNγ, IL-2, TNFα, and IL-6 by CD4+ T cells in vitro, whereas they promoted the production of IL-10. Adoptive transfer of MDSCs reduced both clinical (Image A) and histological arthritis scores (Image B) in vivo, which was accompanied by a decrease in the number of CD4+ T cells and Th17 cells in the draining lymph nodes. Image/graph Conclusions MDSCs in CIA suppress the progression of CIA by inhibiting the pro-inflammatory immune response of CD4+ T cells. These observations suggest that MDSCs play crucial roles in the regulation of autoimmune arthritis, which could be exploited in new cell-based therapies for human rheumatoid arthritis (RA). References Gabrilovich, D. I., and S. Nagaraj. 2009. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9: 162-174. Disclosure of Interest None Declared


Biochemical and Biophysical Research Communications | 2018

Role of allograft inflammatory factor-1 in bleomycin-induced lung fibrosis

Hidetake Nagahara; Takahiro Seno; Aihiro Yamamoto; Hiroshi Obayashi; Takuya Inoue; Takashi Kida; Amane Nakabayashi; Yuji Kukida; Kazuki Fujioka; Wataru Fujii; Ken Murakami; Masataka Kohno; Yutaka Kawahito

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries in a rat ectopic cardiac allograft model. We previously reported that AIF-1 is associated with the pathogenesis of rheumatoid arthritis and skin fibrosis in sclerodermatous graft-versus-host disease mice. Here, we used an animal model of bleomycin-induced lung fibrosis to analyze the expression of AIF-1 and examine its function in lung fibrosis. The results showed that AIF-1 was expressed on lung tissues, specifically macrophages, from mice with bleomycin-induced lung fibrosis. Recombinant AIF-1 increased the production of TGF-β which plays crucial roles in the mechanism of fibrosis by mouse macrophage cell line RAW264.7. Recombinant AIF-1 also increased both the proliferation and migration of lung fibroblasts compared with control group. These results suggest that AIF-1 plays an important role in the mechanism underlying lung fibrosis, and may provide an attractive new therapeutic target.


Annals of the Rheumatic Diseases | 2016

AB0247 A New Disease Activity Biomarker Alternative To CRP under Tocilizumab Therapy for Rheumatoid Arthritis via Peptidomic Analysis

Takahiro Seno; D. Nonaka; Masataka Kohno; H. Sofue; A. Kasahara; R. Sagawa; Takashi Kida; Yuji Kukida; Kazuki Fujioka; Wataru Fujii; Ken Murakami; L.-J. Lee; K. Tanaka; Yutaka Kawahito

Background Tocilizumab, anti-IL-6 receptor monoclonal antibody, is widely used for patients with rheumatoid arthritis. IL-6 is essential for production of C-reactive protein (CRP). Tocilizumab fully inhibit the production of CRP. Therefore, we have difficulty in objective assessment of infection and disease activity because the level of CRP is suppressed under tocilizumab therapy. The development of new biomarker alternative to CRP is needed for daily practice. Objectives To discover new biomarkers alternative to CRP under tocilizumab therapy for rheumatoid arthritis. Methods We registered patients with rheumatoid arthritis treated with tocilizumab. We collected serum samples from those patients at baseline, 4 weeks after the first tocilizumab administration when patients CRP level is almost normal, and 1 year later. And we measured CRP, ESR and clinical disease activity index (CDAI) score.Serum peptidomic analysis was conducted by newly-established one-step direct transfer technology (BLOTCHIP-MS analysis), a rapid quantitative technology for peptidomic analysis. All sample measurements were repeated four times. Statistical analyses of MS spectral data were conducted using ClinProTools version 2.2 (Bruker Daltonics). Results We registered 14 patients and their background is shown in Table 1. The levels of CRP were 1.16±0.99 mg/dl at baseline, 0.02±0.01 mg/dl at 4 weeks and 0.01±0.01mg/dl at 1 year, respectively. Their CDAI score were 22±9.2 at baseline, 15±8.9 at 4 weeks and 3±2.6 at 1 year, respectively. CRP titer decreased to almost normal level at 4 weeks regardless whether CDAI score did not fully decrease. We detect 6 biomarkers, named as PRSJ01 to PRSJ06, by the peptidomic analysis (Table 2). The AUC of diagnostic value of these markers is from 0.742 to 0.858. For example, the level of PRSJ06 significantly decreased 4 weeks (Wilcoxon singed-rank test, p=0.02) and 1 year (Wilcoxon singed-rank test, p=0.003) after first tocilizumab administration (Figure 1). and it was inversely-correlated with CDAI score. Conclusions We detect new disease activity biomarkers alternative to CRP under tocilizumab therapy for rheumatoid arthritis. It is useful for exact evaluation of disease activity and infection during tocilizumab therapy. Disclosure of Interest None declared

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Yutaka Kawahito

Kyoto Prefectural University of Medicine

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Masataka Kohno

Kyoto Prefectural University of Medicine

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Takahiro Seno

Kyoto Prefectural University of Medicine

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Aihiro Yamamoto

Kyoto Prefectural University of Medicine

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Hidetake Nagahara

Kyoto Prefectural University of Medicine

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Ken Murakami

Kyoto Prefectural University of Medicine

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Kazuki Fujioka

Kyoto Prefectural University of Medicine

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Yuji Kukida

Kyoto Prefectural University of Medicine

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Takashi Kida

Kyoto Prefectural University of Medicine

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Amane Nakabayashi

Kyoto Prefectural University of Medicine

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