Researcher Database


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HAYASHI Hidetoshi

FacultyGraduate School of Pharmaceutical Sciences Department of Cell Signaling, Executives
PositionProfessor
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Last Updated :2020/07/02

Researcher Profile and Settings

Education

  •   1982 04  - 1987 03 , The University of Tokyo, Graduate School of Pharmaceutical Sciences
  •   1978 04  - 1982 03 , The University of Tokyo

Degree

  • 博士(薬学), 東京大学

Association Memberships

  • International Cytokine Society
  • the American Society for Cell Biology

Academic & Professional Experience

  •   2008 04  - 現在, Nagoya City University, Graduate School of Pharmaceutical Sciences
  •   1996 01  - 2008 03 , Nagoya City University, Graduate School of Pharmaceutical Sciences
  •   1992 05  - 1995 12 , Nagoya City University, Medicin
  •   1990 04  - 1992 04 , Nagoya City University, Medicin
  •   1989 01  - 1990 03 , Kanazawa University, Faculty of Pharmaceutical Sciences
  •   1987 04  - 1988 12 , Teikyo University, Faculty of Pharma-Science

Research Activities

Research Areas

  • Life sciences, Pharmaceuticals - health and biochemistry
  • Life sciences, Pharmaceuticals - health and biochemistry
  • Life sciences, Tumor biology

Research Interests

    glucose and lipid metabolism, inflammation, cellular stress, Epithelial-Mesenchymal Transition, drug repositioning, ER stress, cancer molecular target drugs, TGF-beta, deubiquitination

Published Papers

  • Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence, Chiharu Miyajima, Yuki Kawarada, Yasumichi Inoue, Chiaki Suzuki, Kana Mitamura, Daisuke Morishita, Nobumichi Ohoka, Takeshi Imamura, Hidetoshi Hayashi, cells, 9, (1) , 01 , Refereed
  • The ubiquitin-specific protease USP17 prevents cellular senescence by stabilizing the methyltransferase SET8 and transcriptionally repressing p21., Keishi Fukuura, Yasumichi Inoue, Chiharu Miyajima, Shin Watanabe, Muneshige Tokugawa, Daisuke Morishita, Nobumichi Ohoka, Masayuki Komada, Hidetoshi Hayashi, Journal of Biological Chemistry, 294, (44) 16429 - 16439, 11 , Refereed
  • Kurarinone from Sophora flavescens roots triggers ATF4 activation and cytostatic effects through PERK phosphorylation, Sakiko Nishikawa, Yuka Itoh, Muneshige Tokugawa, Yasumichi Inoue, Ken ichi Nakashima, Yuka Hori, Chiharu Miyajima, Kou Yoshida, Daisuke Morishita, Nobumichi Ohoka, Makoto Inoue, Hajime Mizukami, Toshiaki Makino, Hidetoshi Hayashi, Molecules, 24, (17) , 08 , Refereed
  • TRB1 negatively regulates gluconeogenesis by suppressing the transcriptional activity of FOXO1, Kaori Tsuzuki, Yuka Itoh, Yasumichi Inoue, Hidetoshi Hayashi, FEBS Letters, 593, (3) 369 - 380, 02 , Refereed
  • Lysine-specific demethylase 1 (LSD1/KDM1A) is a novel target gene of c-myc, Mai Nagasaka, Kaori Tsuzuki, Yu Ozeki, A. Muneshige Tokugawa, Nobumichi Ohoka, Yasumichi Inoue, Hidetoshi Hayashi, Biological and Pharmaceutical Bulletin, 42, (3) 481 - 488, 01 , Refereed
  • Anti-tumorigenic activity of chrysin from oroxylum indicum via non-genotoxic p53 activation through the ATM-Chk2 pathway, Mai Nagasaka, Ryoko Hashimoto, Yasumichi Inoue, Kan'ichiro Ishiuchi, Michiyo Matsuno, Yuka Itoh, Muneshige Tokugawa, Nobumichi Ohoka, Daisuke Morishita, Hajime Mizukami, Toshiaki Makino, Hidetoshi Hayashi, Molecules, 23, (6) , 01 , Refereed
  • The CDK inhibitor p21 is a novel target gene of ATF4 and contributes to cell survival under ER stress, Yasumichi Inoue, Shiori Kawachi, Tsubasa Ohkubo, Mai Nagasaka, Shogo Ito, Keishi Fukuura, Yuka Itoh, Nobumichi Ohoka, Daisuke Morishita, Hidetoshi Hayashi, FEBS Letters, 591, (21) 3682 - 3691, 11 , Refereed
  • TGF-beta induces p53/Smads complex formation in the PAI-1 promoter to activate transcription, Yuki Kawarada, Yasumichi Inoue, Fumihiro Kawasaki, Keishi Fukuura, Koichi Sato, Takahito Tanaka, Yuka Itoh, Hidetoshi Hayashi, SCIENTIFIC REPORTS, 6, 10 , Refereed, Transforming growth factor beta (TGF-beta) signaling facilitates tumor development during the advanced stages of tumorigenesis, but induces cell-cycle arrest for tumor suppression during the early stages. However, the mechanism of functional switching of TGF-beta is still unknown, and it is unclear whether inhibition of TGF-beta signaling results amelioration or exacerbation of cancers. Here we show that the tumor suppressor p53 cooperates with Smad proteins, which are TGF-beta signal transducers, to selectively activate plasminogen activator inhibitor type-1 (PAI-1) transcription. p53 forms a complex with Smad2/3 in the PAI-1 promoter to recruit histone acetyltransferase CREB-binding protein (CBP) and enhance histone H3 acetylation, resulting in transcriptional activation of the PAI-1 gene. Importantly, p53 is required for TGF-beta-induced cytostasis and PAI-1 is involved in the cytostatic activity of TGF-beta in several cell lines. Our results suggest that p53 enhances TGF-beta-induced cytostatic effects by activating PAI-1 transcription, and the functional switching of TGF-beta is partially caused by p53 mutation or p53 inactivation during cancer progression. It is expected that these findings will contribute to optimization of TGF-beta-targeting therapies for cancer.
  • TGF-beta Decreases the Stability of IL-18-Induced IFN-gamma mRNA through the Expression of TGF-beta-Induced Tristetraprolin in KG-1 Cells, Yasumichi Inoue, Kenji Abe, Kikuo Onozaki, Hidetoshi Hayashi, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 38, (4) 536 - 544, 04 , Refereed, We have previously reported that transforming growth factor-beta (TGF-beta) down-regulates interferon-gamma (IFN-gamma) production in an interleukin-18 (IL-18) treated mouse natural killer (NK) cell line, LNK5E6. In LNK5E6 cells, TGF-beta exhibited no inhibition of the IL-18-induced transcription of IFN-gamma, but did stimulate the degradation of IFN-gamma mRNA induced by IL-18. In the present study, we investigated the mechanism of the down-regulatory effects of TGF-beta on IFN-gamma mRNA expression in a human myelomonocytic cell line, KG-1, which produces IFN-gamma in response to IL-18 alone. Interestingly, IL-18 induced the production of the IFN-gamma through the stabilization of IFN-gamma mRNA, but not the enhanced transcription of IFN-gamma gene. The stability of IFN-gamma mRNA was regulated by mRNA destabilizing elements in the 3'untranslated region (UTR) of IFN-gamma mRNA, especially adenylate-uridylate (AU)-rich elements (AREs) in the 5' half of 3'UTR. Tristetraprolin (TTP), one of the ARE-binding proteins, destabilizes IFN-gamma mRNA, and IL-18 repressed the expression of TTP mRNA. Moreover, TGF-beta repressed the IL-18-induced expression of IFN-gamma mRNA through the induction of TTP mRNA to destabilize IFN-gamma mRNA. Our data is the first to reveal that the crosstalk between IL-18 and TGF-beta through the expression of TTP regulates the production of IFN-gamma.
  • A novel transgenic mouse model carrying human tribbles related protein 3 (TRB3) gene and its site specific phenotype, Yuto Sakai, Katsumi Fukamachi, Mitsuru Futakuchi, Ichiro Miyoshi, Hiroyuki Tsuda, Masumi Suzui, Hidetoshi Hayashi, Biological and Pharmaceutical Bulletin, 37, (6) 1068 - 1074, 01 , Refereed
  • Promotive effects of cell proliferation and chromosomal instability induced by tribbles-related protein 3 in mouse mammary tumor cells, Yuto Sakai, Katsumi Fukamachi, Mitsuru Futakuchi, Hidetoshi Hayashi, Masumi Suzui, Oncology Reports, 30, (1) 64 - 70, 07 , Refereed
  • Hypoxia-inducible Factor-1 alpha (HIF1 alpha) Switches on Transient Receptor Potential Ankyrin Repeat 1 (TRPA1) Gene Expression via a Hypoxia Response Element-like Motif to Modulate Cytokine Release, Noriyuki Hatano, Yuka Itoh, Hiroka Suzuki, Yukiko Muraki, Hidetoshi Hayashi, Kikuo Onozaki, Ian C. Wood, David J. Beech, Katsuhiko Muraki, JOURNAL OF BIOLOGICAL CHEMISTRY, 287, (38) 31962 - 31972, 09 , Refereed, Transient receptor potential ankyrin repeat 1 (TRPA1) forms calcium (Ca2+)- and zinc (Zn2+)-permeable ion channels that sense noxious substances. Despite the biological and clinical importance of TRPA1, there is little knowledge of the mechanisms that lead to transcriptional regulation of TRPA1 and of the functional role of transcriptionally induced TRPA1. Here we show induction of TRPA1 by inflammatory mediators and delineate the underlying molecular mechanisms and functional relevance. In human fibroblast-like synoviocytes, key inflammatory mediators (tumor necrosis factor-alpha and interleukin-1 alpha) induced TRPA1 gene expression via nuclear factor-kappa B signaling and downstream activation of the transcription factor hypoxia-inducible factor-1 alpha (HIF1 alpha). HIF1 alpha unexpectedly acted by binding to a specific hypoxia response element-like motif and its flanking regions in the TRPA1 gene. The induced TRPA1 channels, which were intrinsically activated by endogenous hydrogen peroxide and Zn2+, suppressed secretion of interleukin-6 and interleukin-8. The data suggest a previously unrecognized HIF1 alpha mechanism that links inflammatory mediators to ion channel expression.
  • Dihydrotestosterone Inhibits Interleukin-1 alpha or Tumor Necrosis Factor alpha-Induced Proinflammatory Cytokine Production via Androgen Receptor-Dependent Inhibition of Nuclear Factor-kappa B Activation in Rheumatoid Fibroblast-Like Synovial Cell Line, Jian Xu, Yuka Itoh, Hidetoshi Hayashi, Takemasa Takii, Keiji Miyazawa, Kikuo Onozaki, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 34, (11) 1724 - 1730, 11 , Refereed, Rheumatoid arthritis (RA) is a disease with significant gender differences in its prevalence and clinical features. Interleukin (IL)-1 and tumor necrosis factor (TNF) alpha produced by synoviocytes are principle inflammatory and destructive mediators of RA. We found that a potent androgen, 5 alpha-dihydrotestosterone (DHT) inhibits IL-1 alpha-induced production and mRNA expression of IL-8, IL-6 and IL-1 beta from RA patient-derived fibroblast-like synovial cell line MH7A. Promoter analysis of the IL-8 gene revealed that nuclear factor (NF)-kappa B activation is critical for its transcriptional activation by IL-1 alpha, and DHT inhibited the IL-1 alpha-induced NF-kappa B activation in a manner dependent on the androgen receptor (AR). DHT also inhibited the effects of TNF alpha on the cells overexpressed with AR, indicating that sufficient expression level of functional AR was necessary for the inhibitory effect of DHT on TNF alpha. These results suggest that androgen contributes to the prevention against RA and its gender difference by inhibiting IL-1 alpha or TNF alpha-induced proinflammatory cytokine production from synovial fibroblast-like cells by inhibiting NF-kappa B activation in a manner depending on AR.
  • Reduction of transforming growth factor-beta type II receptor is caused by the enhanced ubiquitin-dependent degradation in human renal cell carcinoma, Hirotaka Fukasawa, Tatsuo Yamamoto, Yoshihide Fujigaki, Taro Misaki, Naro Ohashi, Tatsuya Takayama, Sayuri Suzuki, Soichi Mugiya, Toshiaki Oda, Chiharu Uchida, Kyoko Kitagawa, Takayuki Hattori, Hidetoshi Hayashi, Seiichiro Ozono, Masatoshi Kitagawa, Akira Hishida, INTERNATIONAL JOURNAL OF CANCER, 127, (7) 1517 - 1525, 10 , Refereed, Although dysregulation of transforming growth factor-beta (TGF-beta) signalling is implicated in renal carcinogenesis, its precise mechanism is unknown in renal cell carcinoma (RCC) in our study, we investigated Smad-medicated TGF-beta signalling pathway and its regulatory mechanisms in surgical samples from patients with RCC. We found that immunoreactivity for nuclear phosphorylated Smad2 was significantly decreased in RCC compared to normal renal tissues, thereby TGF-beta signaling was suggested to be attenuated in RCC tissues. In accordance with the result transcriptional downregulation of Smad4 and post-transcriptional downregulation of TGF-beta type II receptor (T beta R-II) were frequently found in RCC, we investigated the activities of degradation and ubiquitination of T beta R-II. We found that both proteasome-mediated degradation and ubiquitination of T beta R-II were markedly enhanced in RCC tissues. Moreover, we found that the level of Smad ubiquitination regulatory factor 2 (Smurf2), and the E3 ligase for T beta R-II, was increased in RCC tissues of the patients with higher clinical stages compared to the normal tissues and was inversely correlated with the levels of T beta R-II. Our results suggest that the low T beta R-II protein level is due to augmented ubiquitin-dependent degradation via Smurf2 and might be involved in the attenuation of TGF-beta signaling pathway in RCC.
  • [Interleukin-1(IL-1) alpha, beta, IL-1 receptor (IL-1R), IL-1 receptor antagonist (IL-1ra)]., Hidetoshi Hayashi, Kikuo Onozaki, Nippon Rinsho. Japanese Journal of Clinical Medicine, 68, (Suppl 7) 62 - 66, 01
  • Two mechanistically and temporally distinct NF-κB activation pathways in IL-1 signaling, Kohsuke Yamazaki, Jin Gohda, Atsuhiro Kanayama, Yusei Miyamoto, Hiroaki Sakurai, Masahiro Yamamoto, Shizuo Akira, Hidetoshi Hayashi, Bing Su, Jun Ichiro Inoue, Science Signaling, 2, (93) , 10 , Refereed
  • The Orphan Nuclear Receptor ROR alpha Restrains Adipocyte Differentiation through a Reduction of C/EBP beta Activity and Perilipin Gene Expression, Nobumichi Ohoka, Shogo Kato, Yu Takahashi, Hidetoshi Hayashi, Ryuichiro Sato, MOLECULAR ENDOCRINOLOGY, 23, (6) 759 - 771, 06 , Refereed, The nuclear receptor-type transcription factor retinoic acid receptor-related orphan receptor alpha (ROR alpha) is a multifunctional molecule involved in tissue development and cellular function, such as inflammation, metabolism, and differentiation; however, the role of ROR alpha during adipocyte differentiation has not yet been fully understood. Here we show that ROR alpha inhibits the transcriptional activity of CCAAT/enhancer-binding protein beta (C/EBP beta) without affecting its expression, thereby blocking the induction of both PPAR gamma and C/EBP alpha, resulting in the suppression of C/EBP beta-dependent adipogenesis. ROR alpha interacted with C/EBP alpha so as to repress both the C/EBP beta-p300 association and the C/EBP beta-dependent recruitment of p300 to chromatin. In addition to the inhibitory effect on C/EBP beta function, ROR alpha also prevents the expression of the lipid droplet coating protein gene perilipin by peroxisome proliferators-activated receptor gamma (PPAR gamma), acting through the specific mechanism of its promoter. We identified a suppressive ROR-responsive element overlapping the PPAR-responsive element in the perilipin promoter and verified that ROR alpha competitively antagonizes the binding of PPAR gamma. ROR alpha inhibits PPAR gamma-dependent adipogenesis along with the repression of perilipin induction. These findings suggest that ROR alpha is a novel negative regulator of adipocyte differentiation that acts through dual mechanisms. (Molecular Endocrinology 23: 759-771, 2009)
  • TRB3 suppresses adipocyte differentiation by negatively regulating PPAR gamma transcriptional activity, Yu Takahashi, Nobumichi Ohoka, Hidetoshi Hayashi, Ryuichiro Sato, JOURNAL OF LIPID RESEARCH, 49, (4) 880 - 892, 04 , Refereed, In the course of an effort to identify the regulators for peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent perilipin gene expression, we found that tribbles homolog 3 (TRB3), containing a single kinase domain without enzymatic activity, downregulates PPAR gamma transcriptional activities by protein-protein interaction. We examined the role that TRB3 plays in adipocyte differentiation in 3T3-LI cells. TRB3 gene and protein expression was increased during adipocyte differentiation concomitantly with an increase in the mRNA levels of CCAAT/enhancer binding protein homologous protein. The physical interaction between TRB3 and PPAR gamma was also verified in 3T3-LI adipocytes. Forced TRB3 expression in 3T3-LI cells decreased the mRNA levels of PPAR gamma-target genes and intracellular triglyceride levels, whereas knockdown of TRB3 expression by RNA interference increased them. TRB3 also inhibits PPAR gamma-dependent adipocyte differentiation in lentivirus-mediated PPAR gamma-expressing 3T3-LI cells. These results provide evidence that TRB3 acts as a potent negative regulator of PPAR gamma, a master regulator of adipocyte differentiation, and tightly controls adipogenesis.
  • The interaction with Sp1 and reduction in the activity of histone deacetylase 1 are critical for the constitutive gene expression of IL-1 alpha in human melanoma cells, Kazuaki Enya, Hidetoshi Hayashi, Takemasa Takii, Nobumichi Ohoka, Shinya Kanata, Takashi Okamoto, Kikuo Onosaki, JOURNAL OF LEUKOCYTE BIOLOGY, 83, (1) 190 - 199, 01 , Refereed, A375-6 human melanoma cells are sensitive to the antiproliferative effect of IL-1. After a long period of culturing, we have obtained cells resistant to IL-1. The resistant clone A375-R8 constitutively produced IL-1 alpha. In this study, we identified a sequence, CGCC, located at -48 to -45 upstream of the transcription start site, to be essential for the constitutive IL-1 alpha gene activation. Specificity protein 1 (Sp1) and Sp3 bound to the nucleotide containing the sequence. Although the binding level to the nucleotide and expression level of Sp1 and Sp3 are comparable in A375-R8 and A375-6 cells, transactivation activity of Sp1 is higher in A375-R8 cells as compared with A375-6 cells. Sp3 could not transactivate the IL-1 alpha promoter. These results suggest that Sp1 but not Sp3 is important for IL-1 alpha gene activation. Trichostatin A (TSA), an inhibitor of histone deacetylase (HDAC), greatly augmented the IL-1 alpha promoter activity in A375-6 cells to the level comparable with that in A375-R8 cells. TSA also induced IL-1 alpha mRNA expression in A375-6 cells. Sp1 and Sp3 bound to HDAC1 in A375-R8 and A375-6 cells. The chromatin immunoprecipitation assay revealed the binding of Sp1 and HDAC1 to the promoter region of the IL-1 alpha gene. The activities of HDAC bound to Sp1 and Sp3, and that of HDAC1 was lower in A375-R8 cells as compared with A375-6 cells. These results indicate that the reduction in the activity and interaction of HDAC1 with Sp1 are critical for the constitutive IL-1 alpha gene expression.
  • Dihydrotestosterone inhibits tumor necrosis factor alpha induced Interleukin-1 alpha mRNA expression in rheumatoid fibroblast-like synovial cells, Yuka Itoh, Hidetoshi Hayashi, Jian Xu, Takemasa Takii, Keiji Miyazawa, Hiroyoshi Ariga, Tohru Akahoshi, Yuko Waguri-Nagaya, Takanobu Otsuka, Takashi Okamoto, Kikuo Onozaki, BIOLOGICAL & PHARMACEUTICAL BULLETIN, 30, (6) 1140 - 1143, 06 , Refereed, Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects multiple synovial joints. Proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)alpha play important roles as principle inflammatory and destructive components of the disease. RA is known to be associated with significant gender differences in its prevalence and clinical features. We found that a potent androgen, 5 alpha-dihydrotestosterone (DHT) inhibits IL-1 alpha mRNA expression induced by TNF alpha and the DHT effect was inhibited by an androgen receptor antagonist, hydroxyflutamide (OHF). DHT inhibited the NF-kappa B activation induced by TNF alpha in a manner dependent on the androgen receptor (AR). These results suggest that DHT inhibits the TNF alpha-induced IL-1 alpha mRNA expression by inhibiting NF-kappa B activation, and contributes to the gender differences of the disease.
  • N-acetylneuraminic acid coupled human recombinant TNF alpha exhibits enhanced anti-tumor activity against Meth-A fibrosarcoma and reduced toxicity, Akiko Hayashi, Hidetoshi Hayashi, Taku Chiba, Satoshi Sasayama, Kikuo Onozaki, CANCER IMMUNOLOGY IMMUNOTHERAPY, 56, (4) 555 - 562, 04 , Refereed, In order to study the effect of glycosylation on its biological activities and to develop tumor necrosis factor alpha (TNF alpha) with less deleterious effects, N-acetylneuraminic acid (NeuAc) with a C9 spacer was chemically coupled to human recombinant TNF alpha. NeuAc-coupled TNF alpha (NeuAc-TNF alpha) exhibited reduced activities in vitro by about threefold compared to native TNF alpha. In this study, we examined a variety of TNF alpha activities in vivo. NeuAc-TNF alpha reduced activities in the up-regulation of serum levels of IL-6 and NOx, but comparable activity as native TNF alpha in the down-regulation of the serum level of glucose. However, NeuAc-TNF alpha was more potent than TNF alpha in the up-regulation of the serum level of serum amyloid A (SAA). NeuAc-TNF alpha was less toxic to mice. In addition, NeuAc-TNF alpha exhibited an augmented anti-tumor activity against Meth-A fibrosarcoma without hemorrhagic necrosis. These results indicate that coupling with NeuAc enabled us to develop neoglycoTNF alpha with selective activities in vivo, including enhanced anti-tumor activity but reduced toxicity.
  • Synthesis of glycosylated human tumor necrosis factor alpha coupled with N-acetylneuraminic acid, Akiko Hayashi, Taku Chiba, Hidetoshi Hayashi, Satoshi Sasayama, Toshiyuki Ishiguro, Kikuo Onozaki, CANCER IMMUNOLOGY IMMUNOTHERAPY, 56, (4) 545 - 553, 04 , Refereed, In order to study the effect of glycosylation on its biological activities, and to develop TNF alpha with less deleterious effects, recombinant human TNF alpha was chemically coupled with N-acetylneuraminic acid (NeuAc). NeuAc with C9 spacer was coupled to TNF alpha by acyl azide method. Two glycosylated TNF alpha s, designated L NeuAc-TNF alpha and H NeuAc-TNF alpha, were purified by anion-exchange chromatography. NeuAc coupling to TNF alpha was confirmed by lectin blotting. Average number of carbohydrate molecules introduced per molecule of L NeuAc-TNF alpha and H NeuAc-TNF alpha were estimated to be 1.0 and 1.5, respectively. We examined a variety of TNF alpha activities in vitro, including antiproliferative or cytotoxic activities to tumor cells, proliferative effect on fibroblast cells, stimulatory effects on IL-6 production by melanoma cells and NF-kappa B activation in hepatoma cells. L NeuAc-TNF alpha and H NeuAc-TNF alpha exhibited reduced activities about 1/3 and 1/10 as compared to native TNF alpha in all the activities performed in vitro.
  • 17 beta-estradiol induces IL-1 alpha gene expression in rheumatoid fibroblast-like synovial cells through estrogen receptor alpha (ER alpha) and augmentation of transcriptional activity of Sp1 by dissociating histone deacetylase 2 from ER alpha, Yuka Itoh, Hidetoshi Hayashi, Keiji Miyazawa, Soichi Kojima, Tohru Akahoshi, Kikuo Onozaki, JOURNAL OF IMMUNOLOGY, 178, (5) 3059 - 3066, 03 , Refereed, Rheumatoid arthritis (RA) occurs four times more frequently in women than in men, although the mechanistic basis of the gender difference is unknown. RA is characterized by the overproliferation of synoviocytes producing prointlammatory cytokines such as IL-1. implicated in the pathogenesis of the disease. In this study we examined whether 17 beta-estradiol (E2) induced IL-1 alpha mRNA expression in the rheumatoid fibroblast-like cell line MH7A, as well as in primary synovial cells from RA patients, and investigated the underlying molecular mechanisms. E2 induced IL-1 alpha mRNA expression in both cell types in an estrogen receptor-dependent manner. In MH7A cells ER alpha but not ER beta mediated the effects of E2. Deletion and mutation analysis revealed that a GC-rich region within the IL-1 alpha gene promoter was responsible for the response to E2. EMSAs showed that Sp1 and Sp3 bound to the GC-rich region and that the transcriptional activity of Sp1 was up-regulated by the treatment with E2. Sp1 and ER alpha interacted physically regardless of the presence of E2. Physical interaction was also observed between ER alpha and histone deacetylase 2 (HDAC2), and E2 induced the dissociation of HDAC2 from ER alpha. These results suggest that E2 induces the dissociation of corepressor HDAC2 from ER alpha, which leads to the augmentation of Spl transcriptional activity through the GC-rich region within the IL-1 alpha gene promoter.
  • Transcriptional induction of Smurf2 ubiquitin ligase by TGF-beta, N Ohashi, T Yamamoto, C Uchida, A Togawa, H Fukasawa, Y Fujigaki, S Suzuki, K Kitagawa, T Hattori, T Oda, H Hayashi, A Hishida, M Kitagawa, FEBS LETTERS, 579, (12) 2557 - 2563, 05 , Refereed, Smad ubiquitination regulatory factor 2 (Smurf2), a ubiquitin ligase for Smads, plays critical roles in the regulation of transforming growth factor-beta (TGF-beta)-Smad signaling via ubiquitin-dependent degradation of Smad2 and Smad7. We found that TGF-beta stimulates Smurf2 expression. TGF-beta activated the Smurf2 promoter in a TGF-beta responsive cell lines, whereas IL-1 alpha, PDGF and epidermal growth factor did not. TGF-beta-mediated Smurf2 promoter activation was inhibited by Smad7 or an activin receptor-like kinase 5 inhibitor but not by dominant negative Smad or disruption of Smad-binding elements in the promoter. Moreover, inhibition of the phosphatidil inositol 3 kinase (PI3K)/Akt pathway suppressed TGF-beta-mediated Smurf2 induction. These results suggest that TGF-beta stimulates Smurf2 expression by Smad-independent pathway such as PI3K/Akt pathway via TGF-beta receptor. (c) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
  • Interleukin-1 (IL-1) alpha, beta, IL-1 receptor, IL-1 receptor antagonist (IL-1ra), Hidetoshi Hayashi, Kikuo Onozaki, Nippon rinsho. Japanese journal of clinical medicine, 63, (Suppl 8) 60 - 64, 01
  • TGF-beta down-regulates IL-1 alpha-induced TLR2 expression in murine hepatocytes, T Matsumura, H Hayashi, T Takii, CF Thorn, AS Whitehead, JI Inoue, K Onozaki, JOURNAL OF LEUKOCYTE BIOLOGY, 75, (6) 1056 - 1061, 06 , Refereed, We have previously reported that the proinflammatory cytokine interleukin (IL)-1alpha can up-regulate functional Toll-like receptor 2 (TLR2) expression in primary-cultured murine hepatocytes, and bacterial lipopeptide (BLP) is capable of signaling through TLR2 to induce serum amyloid A (SAA) expression in hepatocytes. In the present study, we investigated the effect of the anti-inflammatory cytokine transforming growth factor-beta (TGF-beta) on TLR2 expression in primary-cultured murine hepatocytes. At the mRNA and protein levels, TGF-beta up-regulated TLR2 expression but inhibited TLR2 expression induced by IL-1alpha at 24 h. BLP-induced SAA promoter activity could be augmented by pretreatment with IL-1alpha but not TGF-beta or the combination of TGF-beta and IL-1alpha. TLR2 promoter activity and nuclear factor (NF)-kappaB activation by IL-1alpha were inhibited by TGF-beta treatment. Pretreatment with TGF-beta strongly suppressed IL-1alpha-induced TLR2 promoter activity and NF-kappaB activation, which was consistent with the down-regulation of type I IL-1 receptor (IL-1RI) mRNA expression. IL-1alpha up-regulated IL-1RI mRNA, but it was inhibited by the treatment with TGF-beta. These results suggest that TGF-beta suppresses the induction of TLR2 expression by IL-1alpha through down-regulation of IL-1RI expression. These results also demonstrate the disparity between IL-1alpha and TGF-beta in regulating TLR2-mediated SAA production in hepatocytes.
  • A potential live vector, foamy virus, directed intra-cellular expression of ovine interferon-tau exhibited the resistance to HIV infection, Y Fujii, Y Murase, K Otake, Y Yokota, S Omoto, H Hayashi, H Okada, N Okada, M Kawai, H Okuyama, K Imakawa, JOURNAL OF VETERINARY MEDICAL SCIENCE, 66, (2) 115 - 121, 02 , Refereed, Interferon-tau (IFN-tau), produced by the embryonic trophectoderm, is a member of type I IFNs required for the establishment of pregnancy in the ruminant ungulates. Although this IFN possesses antiviral activity similar to other type I IFNs, the effectiveness of IFN-tau as an antiviral agent has not been well characterized. To investigate possible antiviral effects of ovine IFN-tau (oIFN-tau), oIFN-tau-GST fusion protein was expressed in B. coli BL21, from which the purified protein isolated possessed anti-viral activity. An apathogenic human foamy virus (hFV) was then used to establish a potential recombinant live vector consisting of oIFN-tau cDNA sense (+) or antisense (-) sequence, oIFN-tau(+)/hFV or oIFN-tau(-)/hFV, respectively. Human hematopoietic and other mammalian cell lines that had been transduced with hFV vector consisting of no oIFN-tau, oIFN-tau(+)/hFV or oIFN-tau(-)/hFV construct were cultured initially for 12 days, and three of cell lines were then maintained for up to 90 days. These cells with oIFN-tau expression directed by hFV exhibited the in vitro cytopathic effect minimally. Transduced cell lines that had been cultured for 90 days were subjected to studies on human immunodeficiency virus type-1 (HIV-1) infection, which was measured with infectivity of viral particles resulted from the GFP inserted T-cell tropic HIV SF2 or macrophage tropic HIV SF162: the number of HIV-1 positive cells was reduced by the hFV driven-intra-cellular oIFN-tau expression. Since oIFN-tau/hFV transduced cells exhibited the resistance to HIV-1 infection and/or replication, oIFN-tau could be considered as one of effective antiviral agents against HIV-1. These results suggest that the hFV genome could be an effective recombinant live vector for the expression of a targeted gene in various cell types.
  • Contribution of the Constitutive and Inducible Degradation of Smad3 by the Ubiquitin-Proteasome Pathway to Transforming Growth Factor-β Signaling, Yasumichi Inoue, Masatoshi Kitagawa, Kikuo Onozaki, Hidetoshi Hayashi, Journal of Interferon and Cytokine Research, 24, (4) 43 - 54, 01 , Refereed
  • TRAF6-NF-kappa B pathway is essential for interleukin-1-induced TLR2 expression and its functional response to TLR2 ligand in murine hepatocytes, T Matsumura, T Degawa, T Takii, H Hayashi, T Okamoto, J Inoue, K Onozaki, IMMUNOLOGY, 109, (1) 127 - 136, 05 , Refereed, We have previously reported that the expressions of TLR2 and TLR4 mRNA are differentially regulated in mouse liver and in the parenchymal cells. In the present study, we investigated the mechanism of the up-regulatory effects of interleukin-1alpha (IL-1alpha), tumour necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), or bacterial lipoprotein (BLP) on TLR2 mRNA expression in primary cultured murine hepatocytes. Although TLR2 mRNA stability was not affected, these treatments enhanced NF-kappaB activity and TLR2 gene transcription simultaneously. The up-regulation of TLR2 transcription in response to these reagents was completely inhibited by blocking the NF-kappaB activation pathway, demonstrating a pivotal role of NF-kappaB activation in the regulation of hepatocyte TLR2 transcription. The expression of TLR2 protein by hepatocytes was also remarkably up-regulated by IL-1alpha and, to a lesser extent, by TNF-alpha as well, but not by LPS or BLP. In addition, pretreatment of mice with IL-1alpha markedly increased the BLP (a ligand for TLR2)-induced serum level of serum amyloid A (SAA), an acute-phase protein predominantly produced by hepatocytes, indicating that IL-1alpha may also up-regulate functional TLR2 in vivo . These results demonstrate that IL-1alpha, through activating the TRAF6-NF-kappaB pathway, serves as the most potent inducer for TLR2 up-regulation, and plays an important role in the regulation of hepatocyte functions by augmenting the hepatocyte response to bacteria or bacterial products.
  • TGF beta down-regulates IFN-gamma production in IL-18 treated NK cell line LNK5E6, H Hayashi, Y Inoue, H Tsutsui, H Okamura, K Nakanishi, K Onozaki, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 300, (4) 980 - 985, 01 , Refereed, Transforming growth factor beta (TGFbeta) is a critical immunosuppressive cytokine that inhibits the cell-mediated immune responses partly via inhibition of immunostimulatory cytokine production from T cells, NK cells, and macrophages. Here we investigated the effect of TGFbeta on NK cell activation induced by interleukin 18 (IL-18) using a murine NK cell line LNK5E6. IL-18 activated LNK5E6 cells to produce antiviral activity against vesicular stomatitis virus (VSV) and TGFbeta inhibited this activation. TGFbeta inhibited interferon-gamma (IFN-gamma) production in LNK5E6 cells treated with IL-18. TGFbeta also suppressed the IL-18 induced mRNA expression of IFN-gamma Moreover, TGFbeta did not affect the transcriptional activity of IFN-gamma but decreased the half-life of IFN-gamma mRNAinduced by IL-18. These results suggest that the destabilization of IFN-gamma mRNA induced by TGFbeta leads to the inhibition of antiviral activity and IFN-gamma production in IL-18 stimulated LNK5E6 cells. (C) 2002 Elsevier Science (USA). All rights reserved.
  • Synthesis and biological activities in vitro and in vivo of glycosylated human interleukin-1 alpha, neoglyco IL-1 alpha, coupled with N-acetylneuraminyl-galactose, M Ootsubo, T Chiba, Y Kobayashi, H Hayashi, A Hayashi, K Onozaki, GLYCOCONJUGATE JOURNAL, 20, (2) 119 - 131, Refereed, In order to study the effect of glycosylation on its biological activities, and to develop IL-1alpha with less deleterious effects, recombinant human IL-1alpha was chemically coupled with N-acetylneuraminic acid (alpha1-6) galactose (Neu5Ac-Gal). Glycosylated IL-1alpha (Neu5Ac-Gal-IL-1alpha) was purified by anion-exchange chromatography and average number of carbohydrate molecules introduced per molecule of IL-1alpha was 2.5. Neu5Ac-Gal- IL-1alpha exhibited reduced activities about 1/15-fold compared to IL-1alpha in all the activities performed in vitro. Binding affinities of Neu5Ac-Gal-IL-1alpha to Type I and Type II IL-1 receptors were decreased to 1/15 and 1/10, respectively. Neu5Ac-Gal-IL-1alpha exhibited reduction in activities in vivo, including induction of serum amyloid A and NOx, and down-regulation of serum glucose. However, Neu5Ac-Gal-IL-1alpha exhibited comparable activity to IL-1alpha in improvement of the recovery of peripheral white blood cells from myelosuppression in 5-fluorouracil-treated mice. In addition, tissue level of Neu5Ac-Gal-IL-1alpha was relatively high compared to IL-1alpha. These results indicate that coupling with Neu5Ac-Gal enabled us to develop neoIL-1alpha with selective activities in vivo.
  • CHOP, a basic leucine zipper transcriptional factor, contributes to the antiproliferative effect of IL-1 on A375 human melanoma cells through augmenting transcription of IL-6, T. Hattori, S. Itoh, H. Hayashi, T. Chiba, T. Takii, K. Yoshizaki, K. Onozaki, Journal of Interferon and Cytokine Research, 21, (5) 323 - 332, 08 , Refereed
  • Activation of two distinct anti-proliferative pathways, apoptosis and p38 MAP kinase-dependent cell cycle arrest, by tumor necrosis factor in human melanoma cell line A375, T. Hattori, H. Hayashi, T. Chiba, K. Onozaki, European Cytokine Network, 12, (2) 244 - 252, 06 , Refereed
  • Glycosylated human interleukin-1 alpha, neoglyco IL-1 alpha, coupled with N-acetylneuraminic acid exhibits selective activities in vivo and altered tissue distribution, S Sasayama, K Moriya, T Chiba, T Matsumura, H Hayashi, A Hayashi, K Onozaki, GLYCOCONJUGATE JOURNAL, 17, (6) 353 - 359, 06 , Refereed, In order to study the effect of glycosylation on its biological activities and to develop IL-1 with less deleterious effects, N-acetylneuraminic acid (NeuAc) with C9 spacer was chemically coupled to human recombinant IL-1 alpha. NeuAc-coupled IL-1 alpha (NeuAc-IL-1 alpha) exhibited reduced activities in vitro and receptor-binding affinities by about ten times compared to IL-1 alpha. In this study, we examined a variety of IL-1 activities in vivo. NeuAc-IL-1 alpha exhibited a marked reduction in the activity to up-regulate serum IL-6, moderate reduction in the activities to up-regulate serum amyloid A and NOx. However, it exhibited comparable activities as IL-1 alpha to down-regulate serum glucose and to improve the recovery of peripheral white blood cells from myelosuppression in 5-fluorouracil-treated mice. In addition, tissue level of NeuAc-IL-1 alpha was high compared to IL-1 alpha. These results indicate that coupling with NeuAc enabled us to develop neo-IL-1 with selective activities in vivo and enhanced tissue level.
  • In vitro biological activities of glycosylated human interleukin-1α, neoglyco IL-1α, coupled with N-acetylneuraminic acid, Kayoko Moriya, Taku Chiba, Sachi Nabeshima, Hidetoshi Hayashi, Kikuo Onozaki, Glycoconjugate Journal, 16, (9) 563 - 568, 12 , Refereed
  • Synthesis of glycosylated human interleukin-1α, neoglyco IL-1α, coupled with N-acetylneuraminic acid, Taku Chiba, Kayoko Moriya, Sachi Nabeshima, Hidetoshi Hayashi, Yutaka Kobayashi, Satoshi Sasayama, Kikuo Onozaki, Glycoconjugate Journal, 16, (9) 499 - 505, 12 , Refereed
  • Tyrosine kinase is essential for the constitutive expression of type I interleukin-1 receptor in human fibroblast cells, Takemasa Takii, Atsushi Ito, Sachiko Kawashima, Ayako Ninomiya, Takayuki Matsumura, Hidetoshi Hayashi, Kikuo Onozaki, European Cytokine Network, 10, (2) 237 - 245, 07 , Refereed
  • Interleukin-1 (IL-1), IL-1 receptor, IL-1 receptor antagonist (IL-1ra), H. Hayashi, K. Onozaki, Nippon rinsho. Japanese journal of clinical medicine, 57 Suppl, 769 - 774, 01 01
  • Molecular analysis of constitutive IL-1α gene expression in human melanoma cells: Autocrine stimulation through NF-κB activation by endogenous IL-1α, Hiroaki Kimura, Yoshitaka Inukai, Takemasa Takii, Yasuji Furutani, Yayoi Shibata, Hidetoshi Hayashi, Shinsaku Sakurada, Takashi Okamoto, Jun Ichiro Inoue, Yasukazu Oomoto, Kikuo Onozaki, Cytokine, 10, (11) 872 - 879, 01 , Refereed
  • Resistance to IL-1 anti-proliferative effect, accompanied by characteristics of advanced melanoma, permits invasion of human melanoma cells in vitro, but not metastasis in the nude mouse, Hidetoshi Hayashi, Reiko Shimizu, Kaori Fujii, Saotomo Itoh, De Yang, Kikuo Onozaki, International Journal of Cancer, 71, (3) 416 - 421, 06 , Refereed
  • Identification of a novel growth-promoting factor with a wide target cell spectrum from various tumor cells as catalase, Tomomi Miyamoto, Masaru Hayashi, Akihiko Takeuchi, Takayuki Okamoto, Sachiko Kawashima, Takemasa Takii, Hidetoshi Hayashi, Kikuo Onozaki, Journal of Biochemistry, 120, (4) 725 - 730, 01 , Refereed
  • Molecular cloning of human antizyme cDNA, De Yang, Takemasa Takii, Hidetoshi Hayashi, Saotomo Itoh, Masaru Hayashi, Kikuo Onozaki, Biochemistry and Molecular Biology International, 38, (5) 957 - 964, 01
  • A high α-linolenate diet has no significant effect on interleukin-1 production but suppresses the loss of body weight in lipopolysaccharide-treated mice, Shiro Watanabe, Hidenori Ito, Tetsuyuki Kobayashi, Hidetoshi Hayashi, Kikuo Onozaki, Harumi Okuyama, Journal of Nutritional Immunology, 3, 61 - 70, 07
  • Type I and Type II Interferons Upregulate Functional Type I Interleukin-1 Receptor in a Human Fibroblast Cell Line TIG-1, Takemasa Takii, Noriyuki Niki, de Yang, Hiroaki Kimura, Atsushi Ito, Hidetoshi Hayashi, Kikuo Onozaki, Journal of Interferon and Cytokine Research, 15, (12) 1065 - 1073, 01 , Refereed
  • Glycosylated Human Recombinant Interleukin-1α, Neo Interleukin-1α, with D-Mannose Dimer Exhibits Selective Activities in Vivo, Yutaka Takei, Taku Chiba, Kaoru Wada, Hidetoshi Hayashi, Masaaki Yamada, Junji Kuwashima, Kikuo Onozaki, Journal of Interferon and Cytokine Research, 15, (8) 713 - 719, 01 , Refereed
  • Ubiquitous interleukin-1α in fetal bovine serum may mislead the experimental results in vitro, S. Hida, A. Takeuchi, H. Hayashi, T. Yano, S. J. Hopkins, K. Onozaki, European Cytokine Network, 6, (2) 121 - 126, 01 , Refereed
  • RESISTANCE TO THE ANTIPROLIFERATIVE EFFECT OF IL-1 ON HUMAN-MELANOMA CELL-LINE IS ASSOCIATED WITH ENDOGENOUS PRODUCTION OF IL-1 AND IL-6, M ARAKI, T YANO, H HAYASHI, T TAKII, K SUZUKI, K ONOZAKI, INTERNATIONAL JOURNAL OF CANCER, 56, (2) 275 - 280, 01 , Refereed, A human melanoma cell line (A375-6) became resistant to the anti-proliferative effect of human IL-1 after a long period of culture. Two stable resistant sub-clones were obtained, and the mechanism of the IL-1 resistance was investigated. Resistant cells, but not sensitive cells, appeared to produce constitutively IL-1 activity. The activity was neutralized by anti-IL-1alpha antibody but not by anti-IL-1beta antibody. Resistant cells expressed IL-1alpha but not IL-1beta mRNA. Therefore, the resistant cells appeared to produce IL-1alpha. mRNA for IL-1 receptor antagonist (IL-1 Ra) was not detected in resistant cells, indicating that the resistance is not attributable to IL-IRa. These resistant cells were also resistant to the anti-proliferative effect of human IL-6, but not to that of human TNF. Resistant cells appeared to produce constitutively IL-6 more than sensitive cells, and IL-6 production both in sensitive and in resistant cells was augmented by exogenous IL-1. Furthermore, constitutive production of IL-6 in resistant cells was inhibited by IL-IRa. Type I IL-1 receptor (IL-1R) mRNA was expressed equally in resistant and sensitive cells. These data indicate that the resistance is not the result of loss of functional IL-1R and that IL-1 induces IL-6 in an autocrine manner. It is, therefore, conceivable that endogenous IL-1 and IL-6 contribute to IL-1 resistance. (C) 1994 Wiley-Liss, Inc.
  • Differences in interleukin 1 (IL-1), IL-6, tumor necrosis factor and IL-1 receptor antagonist production by human monocytes stimulated with muramyl dipeptide (MDP) and its stearoyl derivative, romurtide, Katsuya Suzuki, Keiko Torii, Shigeaki Hida, Hidetoshi Hayashi, Yoshio Hiyama, Yasukazu Oomoto, Takemasa Takii, Taku Chiba, Kikuo Onozaki, Immunopharmacology, 28, (1) 31 - 38, 01 , Refereed
  • Interleukin-1 down-regulates type I interleukin 1 receptor mRNA expression in a human fibroblast cell line TIG-1 in the absence of prostaglandin E2 synthesis, T. Takii, H. Hayashi, T. Marunouchi, K. Onozaki, Lymphokine and Cytokine Research, 13, (3) 213 - 219, 01 , Refereed
  • Novel growth promoting activity with a wide target cell spectrum is present in extracts of various cell types, T. Miyamoto, A. Takeuchi, H. Hayashi, K. Onozaki, Biochemistry and Molecular Biology International, 32, (5) 973 - 981, 01 , Refereed
  • Development of glycosylated human interleukin-1α, neoglyco IL-1α, coupled with D-mannose dimer: Synthesis and biological activities in vitro, Y. Takei, K. Wada, T. Chiba, H. Hayashi, H. Ishihara, K. Onozaki, Lymphokine and Cytokine Research, 13, (4) 265 - 270, 01 , Refereed
  • SYNTHESIS OF IMMUNOSUPPRESSIVE NEOGLYCOPROTEINS - BOVINE SERUM-ALBUMIN COUPLED WITH 8-(HYDRAZINOCARBONYL)OCTYL 4 OR 6-O-ALPHA-D-MANNOPYRANOSYL-ALPHA-D-MANNOPYRANOSIDE, K WADA, T CHIBA, Y TAKEI, H ISHIHARA, H HAYASHI, K ONOZAKI, JOURNAL OF CARBOHYDRATE CHEMISTRY, 13, (7) 941 - 965, Recombinant cytokines generated by bacteria, especially E. coli, are nonglycosylated. To investigate the effects of carbohydrates on their activities, we attempted to develop new cytokines by introduction of carbohydrates. As a model we synthesized neoglycoproteins in which potential immunoregulatory carbohydrates were coupled to bovine serum albumin(BSA). Mannose dimers with C9 spacer, Man alpha 1-6Man, which is reported to be immunosuppressive, and a reference substance Man alpha 1-4Man were synthesized as follows. Benzylidenation of 8-(methoxycarbonyl)octyl alpha-D-mannopyranoside (10), followed by acetylation and cleavage of the benzylidene acetal, gave a glycosyl acceptor (13) with a free hydroxyl group in the C-4 position. Glycosylation of 13 with acetobromomannose (8), followed by debenzylation, deacetylation, and hydrazidation, gave 8-(hydrazinocarbonyl)octyl 4-O-alpha-D-mannopyranosyl-alpha-D-mannopyranoside (1). Total yield of 1 from 10 was 25.1%. Tritylation of 10, followed by acetylation and detritylation, gave a glycosyl acceptor(18) with a free hydroxyl group in the C-6 position. Analogous condensation of 18 with 8, followed by deacetylation and hydrazidation, gave 8-(hydrazinocarbonyl)octyl 6-O-alpha-D-mannopyranosyl-alpha-D-mannopyranoside (2). Total yield of 2 from 10 was 22.9%. These mannose dimers were coupled to BSA by the acyl azide method. Using the antibodies against the mannose dimers, an enzyme linked immunosorbent assay (ELISA) was established to measure the small amount of mannose dimers coupled to proteins. These two neoglycoproteins appeared to inhibit the antigen-specific human T cell proliferation over 100 fold more efficiently than free mannose dimers.
  • Differential production of interleukin 1 (IL-1), IL-6, tumor necrosis factor, and IL-1 receptor antagonist by human monocytes stimulated with Mycobacterium leprae and M. bovis BCG, K. Suzuki, Y. Fukutomi, M. Matsuoka, K. Torii, H. Hayashi, T. Takii, Y. Oomoto, K. Onozaki, International Journal of Leprosy, 61, (4) 609 - 618, 12 , Refereed
  • Development of neoglycoproteins conjugated with natural oligosaccharides through carboxyl residues of proteins and its application to recombinant human interleukin 1, H. Ishihara, T. Chiba, A. Takeuchi, H. Hayashi, Y. Takei, T. Takii, K. Onozaki, Biochemistry and Molecular Biology International, 31, (3) 527 - 535, 01 , Refereed
  • Interleukin‐1 up‐regulates transcription of its own receptor in a human fibroblast cell line TIG‐1: role of endogenous PGE2 and cAMP, Takemasa Takii, Tohru Akahoshi, Koichi Kato, Hidetoshi Hayashi, Tohru Marunouchi, Kikuo Onozaki, European Journal of Immunology, 22, (5) 1221 - 1227, 01 , Refereed
  • Three Types of Membranous ATPase on Rat Liver Lysosomes, Hidetoshi Hayashi, Kunizo Arai, Osamu Sato, Akiyoshi Shimaya, Yoshimichi Sai, Shoji Ohkuma, Chemical and Pharmaceutical Bulletin, 40, (10) 2783 - 2786, 01 , Refereed
  • EFFECT OF DIETARY ALPHA-LINOLENATE LINOLEATE BALANCE ON LIPOPOLYSACCHARIDE-INDUCED TUMOR-NECROSIS-FACTOR PRODUCTION IN MOUSE MACROPHAGES, S WATANABE, H HAYASHI, K ONOZAKI, H OKUYAMA, LIFE SCIENCES, 48, (21) 2013 - 2020, Refereed, We examined the effect of dietary alpha-linolenate (18:3n-3)/linoleate (18:2n-6) balance on lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF) production in mouse macrophages. Resident and casein-induced peritoneal macrophages from mice fed a high alpha-linolenate diet produced a higher amount of TNF than in the high linoleate diet group. However, TNF production was not affected by the dietary alpha-linolenate/linoleate balance when thioglycollate- and complete Freund's adjuvant-induced macrophages were stimulated with LPS. Serum TNF levels of mice intraperitoneally injected with LPS was also higher in the high alpha-linolenate group than in the high linoleate group. These diets affected the n-3/n-6 ratios of 20 and 22 carbon highly unsaturated fatty acids in macrophage lipids. Thus, the dietary enrichment with alpha-linolenate was found to enhance TNF production of macrophages isolated under limited conditions.
  • Induction by platelet activating factor of candidacidal activity in guinea pig bone marrow cells, I. Kudo, H. Hayashi, T. Kato, R. Nozawa, S. Nojima, K. Inoue, International Journal of Immunopharmacology, 10, 01 01
  • Activation of guinea pig peritoneal macrophages by platelet-activating factor in free form or incorporated into liposomes., K. Inoue, H. Hayashi, I. Kudo, S. Tsushima, H. Nomura, S. Nojima, Advances in prostaglandin, thromboxane, and leukotriene research, 15, 711 - 713, 12 , Refereed

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  • 腫瘍細胞に高発現するdecoy kinase TRB3の機能解析,   2006 04  - 2008 03

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