研究者業績

棚元 憲一

タナモト ケンイチ  (TANAMOTO KEN'ICHI)

基本情報

所属
武蔵野大学 薬学部薬学科 教授
学位
学士(東京大学)
博士(東京大学)

J-GLOBAL ID
200901064998242955
researchmap会員ID
0000041232

学歴

 1

委員歴

 7

受賞

 1

論文

 11
  • Kei-ichi Sugiyama, Masashi Muroi, Mawo Kinoshita, Osamu Hamada, Yuji Minai, Yoshiko Sugita-Konishi, Yoichi Kamata, Ken-ichi Tanamoto
    JOURNAL OF TOXICOLOGICAL SCIENCES 41(2) 273-279 2016年4月  査読有り
    Macrophages induce the innate immunity by recognizing pathogens through Toll-like receptors (TLRs), which sense pathogen-associated molecular patterns. Myeloid differentiation factor 88 (MyD88), which is an essential adaptor molecule for most TLRs, mediates the induction of inflammatory cytokines through nuclear factor kappa B (NF-kappa B). Trichothecene mycotoxin deoxynivalenol (DON) shows immunotoxic effects by interrupting inflammatory mediators produced by activated macrophages. The present study investigates the effect of DON on NF-kappa B in activated macrophages through MyD88-dependent pathways. DON inhibited NF-kappa B-dependent reporter activity induced by MyD88-dependent TLR agonists. In addition, lipopolysaccharide-induced phosphorylation of interleukin-1 receptor-associated kinase 1 and inhibitor kappa B alpha were attenuated by DON. Furthermore, DON downregulated the expression level of MyD88. These results suggest that DON inhibits NF-kappa B activation in macrophages stimulated with TLR ligands via MyD88-dependent TLR signals. Therefore exposure to DON may lead to the inhibition of MyD88-dependent pathway of TLR signaling
  • Masashi Muroi, Ken-ichi Tanamoto
    TOXICOLOGY LETTERS 235(3) 199-205 2015年6月  査読有り
    The NLRP3 inflammasome, composed of caspase-1, NLRP3 and ASC, plays a critical role in the clearance of microbial pathogens. Here, we found that the treatment of mouse macrophages with the zinc-containing dithiocarbamate ziram, a widely used fungicide in agriculture, caused a decrease in pro-caspase-1 and NLRP3 levels while not affecting ASC level. Ziram did not affect levels of pro-caspase-1 and NLRP3 mRNA, and no cleavage products of pro-caspase-1 including p10 subunit, which is an autocleavage product of pro-caspase-1, were detected, indicating that the decrease was associated with degradation of these proteins. The decrease was inhibited by SH-type antioxidants, N-acetyl cysteine, dithiothreitol and 2-mercaptoethanol, or a metal chelator EDTA but not by inhibitors of proteasome, lysosomes, autophagy and matrix metalloproteases. Thiram, a comparator for ziram that does not contain zinc, showed a weaker decrease in protein levels. Furthermore, the zinc-containing dithiocarbamate, zinc diethyldithiocarbamate, efficiently decreased the levels of pro-caspase-1 and NLRP3, whereas dithiocarbamates, dimethyldithiocarbamate and diethyldithiocarbamate without zinc, were less active. The organic zinc compound [3,4-toluenedithiolato(2-)] zinc hydrate did not induce a decrease in protein levels. Ziram also inhibited IL-1 beta production by macrophages in response to lipopolysaccharide and bacterial clearance during Salmonella infection of macrophage cells. These results indicate that ziram causes degradation of pro-caspase-1 and NLRP3 in a zinc-and oxidative property-dependent manner and suggest that exposure to ziram may compromise the clearance of microbial pathogens. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
  • Takaaki Kitajima, Masashi Muroi, Naomi Yamashita, Ken-ichi Tanamoto
    BIOLOGICAL & PHARMACEUTICAL BULLETIN 37(1) 74-80 2014年1月  査読有り
    Body and excrement extracts from Dermatophagoides Prime were used to study stimulation of Toll-like receptors (TLRs). The excrement extract stimulated nuclear factor (NF)-kappa B-dependent reporter activity to an extent similar to lipopolysaccharide (LPS) in a mouse macrophage cell line, J774A.1, but the activity of the body extract was negligible. The excrement extract also activated NF-kappa B in HEK293 cells expressing TLR1/TLR2, TLR2/TLR6 and CD14/TLR4/MD-2, whereas no activation was observed in cells expressing TLR3, TLR5, TLR7, TLR8 or TLR9. Although the excrement extract required co-expression of CD14, TLR4 and MD-2 in HEK293 cells to activate NF-kappa B, efficient activation was still observed in I-13.35 cells, a bone-marrow macrophage cell line established from LPS-hypo-responsive C3H/HeJ mice. The excrement extract activated NF-kappa B in HEK293 cells expressing TLR2 alone, but the activation was significantly increased by co-expression of CD14. Polymyxin B inhibited CD14/TLR4/MD-2- and CD14/TLR2-mediated activation of NF-kappa B but not the activation in I-13.35 cells. These results indicate that CD14/TLR4/MD-2-dependent and CD14/TLR2-dependent mechanisms are involved in the activation of NF-kappa B by the excrement extract of D. farinae and suggest that the extract also contains substances that activate NF-kappa B through non-TLR-mediated mechanisms.
  • Naina Shah, Montserrat Montes de Oca, Maria Jover-Cobos, Ken-ichi Tanamoto, Masashi Muroi, Kei-ichi Sugiyama, Nathan A. Davies, Rajeshwar P. Mookerjee, Dipok Kumar Dhar, Rajiv Jalan
    LIVER TRANSPLANTATION 19(7) 751-761 2013年7月  査読有り
    Strategies for the prevention of multiorgan dysfunction (MOD) in acetaminophen (APAP)-induced acute liver failure (ALF) are an unmet need. Our study tested the hypothesis that sterile inflammation induced by APAP in a mouse model would activate toll-like receptor 4 (TLR4) in the liver and extrahepatic organs and lead to the progression of ALF and MOD and that the administration of the novel TLR4 antagonist STM28 (a peptide formed of 17 amino-acids) would prevent liver injury and associated MOD. ALF and, subsequently, MOD were induced in TLR4-knockout (KO) mice (B6.B10ScN-Tlr4 (lpsdel) /JthJ) and wild-type (WT) mice (C57BL/6) with APAP (500 mg/kg). A second set of experiments was conducted to evaluate the effects of a pretreatment with a novel TLR4 antagonist, STM28, on APAP-induced MOD in CD1 mice. Animals were sacrificed at the coma stage, and plasma, peripheral blood cells, liver, kidneys, and brain were collected. Biochemistry values and cytokines were measured. Liver and kidneys were studied histologically and were stained for TLR4 and activated Kupffer cells, and the expression of nuclear factor kappa B-p65 was quantified with western blotting. Brain water was measured in the frontal cortex. After APAP administration, TLR4-KO (NFkBp65) mice were relatively protected from liver necrosis and end-organ dysfunction and had significantly better survival than WT controls (P < 0.01). STM28 attenuated liver injury and necrosis, reduced creatinine levels, and delayed the time to a coma significantly. The increases in cytokines in the plasma and liver, including TLR4 expression and the activation of Kupffer cells, after APAP administration were reduced significantly in the STM28-treated animals. The increased number of circulating myeloid cells was reduced significantly after STM28 treatment. In conclusion, these data provide evidence for an important role of the TLR4 antagonist in the prevention of the progression of APAP-induced ALF and MOD. Liver Transpl 19:751-761, 2013. (C) 2013 AASLD.
  • Norihiko Ogura, Masashi Muroi, Yuka Sugiura, Ken-ichi Tanamoto
    PATHOGENS AND DISEASE 67(3) 199-205 2013年4月  査読有り
    We investigated the difference in the effect of synthetic lipid A compounds on MyD88-dependent and -independent Toll-like receptor 4 (TLR4) signaling in mouse macrophage cells. At higher concentrations, Escherichia coli-type hexa-acylated lipid A 506, Salmonella-type hepta-acylated lipid A 516, the lipid A precursor lipid IVa and monophosphoryl lipid A induced similar levels of production of the MyD88-dependent cytokine IL-1 beta although their potencies varied, whereas the maximum production of the MyD88-independent cytokine RANTES induced by lipid IVa was less than 50% that of other lipid A compounds. A maximum level of NF-kappa B activation, which is involved in IL-1 beta gene transcription, was also induced to a similar level by these four lipid A compounds, while the maximum level of IFN-beta promoter activity induced during MyD88-independent signaling was also less than 50% for lipid IVa stimulation compared with other lipid A compounds. Early I kappa B alpha phosphorylation activated by MyD88-dependent signaling was similarly induced by 506 and lipid IVa, whereas lipid IVa barely stimulated the phosphorylation of IRF3, a MyD88-independent transcription factor, although efficient phosphorylation was observed with 506 stimulation. These results indicate that lipid IVa has limited activity toward MyD88-independent signaling of TLR4, in macrophage cell lines, despite having efficient activity in the MyD88-dependent pathway.
  • 室井正志, 杉浦友香, 廣野泰亮
    医薬品医療機器レギュラトリーサイエンス 44 177-182 2013年  
  • 杉浦友香, 廣野泰亮, 室井正志
    日本防菌防黴学会誌 44 187-196 2013年  査読有り
  • Masashi Muroi, Ken-ichi Tanamoto
    BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 1823(2) 255-263 2012年2月  
    TRAF6 plays a crucial role in signal transduction of the Toll-like receptor (TLR). It has been reported that TRAF6 catalyzes the formation of unique Lys(63)-linked polyubiquitin chains, which do not lead to proteasome-mediated degradation. Here we found that stimulation of J774.1 cells with various TLR ligands led to decreases in TRAF6 protein levels that occurred at a slower rate than I kappa B alpha degradation. The decrease in TRAF6 was inhibited by proteasome inhibitors MG-132, lactacystin and N-acetyl-leucyl-leucyl-norleucinal. Among intracellular TLR signaling molecules MyD88, IRAK-4, IRAK-1, TRAF6, and IKK beta, only IRAK-1 expression downregulated TRAF6 in HEK293 cells. The amount of TRAF6 expressed either transiently or stably was also reduced by co-expression of IRAK-1 and no TRAF6 cleavage products were detected. The levels of either a TRAF6 N-terminal deletion mutant or a ubiquitin ligase-defective mutant were not affected by IRAK-1 expression. Downregulation of TRAF6 required the TRAF6-binding site (Glu(544), Glu(587), Glu(766)) of IRAK-1 but not its catalytic site (Asp(340)). Upon IRAK-1 transfection, no significant TRAF6 ubiquitination was detected. Instead, TRAF6-associated IRAK-1 was ubiquitinated with both Lys(48)- and Lys(63)-linked polyubiquitin chains. TRAF6 downregulation was inhibited by co-expression of the E3 ubiquitin ligase Pellino 3, whose Lys(63)-linked polyubiquitination on IRAK-1 is reported to compete with Lys(48)-linked IRAK-1 polyubiquitination. Expression of IRAK-1 inhibited I kappa B alpha phosphorylation in response to TLR2 stimulation. These results indicate that stimulation of TLRs induces proteasome-dependent downregulation of TRAF6. We conclude that TRAF6 associated with ubiquitinated IRAK-1 is degraded together by the proteasome and that IRAK-1 possesses a negative regulatory role on TLR signaling. (C) 2011 Elsevier B.V. All rights reserved.
  • Muroi M, Igarashi M, Shima K, Nakagawa Y, Fujiwake H
    医薬品医療機器レギュラトリーサイエンス 41 890-894 2010年  

MISC

 172
  • Akiyama T, Yamazaki T
    Shokuhin Eiseigaku Zasshi. 52(1) 40-46 2011年  査読有り
  • Takahiro Ohnishi, Masashi Muroi, Ken-ichi Tanamoto
    MICROBIOLOGY AND IMMUNOLOGY 54(2) 74-80 2010年2月  
    The effects of the soluble forms of the endotoxin receptor molecules sMD-2 and sCD14 on bacterial growth were studied. When Escherichia coli and Bacillus subtilis were incubated at 37 degrees C for 18 hr with either sMD-2 or sCD14, growth of these bacteria was significantly inhibited as evaluated by viable cell counts and NADPH/NADH activity. A mutant of sCD14 (sCD14d57-64) lacking a region essential for LPS binding did not inhibit the growth of E. coli, whereas this mutant did inhibit the growth of B. subtilis. Addition of excess PG to the bacterial culture reversed the inhibitory effect of sMD-2 on the growth of B. subtilis, but not on the growth of E. coli. Furthermore, when evaluated by ELISA, both sMD-2 and sCD14 bound specifically to PG. Taken together, these results indicate that sMD-2 and sCD14 inhibit the growth of both Gram-positive and Gram-negative bacteria and further suggest that binding to PG and LPS is involved in the inhibitory effect of sMD-2 on Gram-positive bacteria and of sCD14 on Gram-negative bacteria, respectively.
  • Kei-ichi Sugiyama, Masashi Muroi, Ken-ichi Tanamoto, Motohiro Nishijima, Yoshiko Sugita-Konishi
    TOXICOLOGY LETTERS 192(2) 150-154 2010年2月  
    Deoxynivalenol (DON) and nivalenol (NIV), trichothecene mycotoxins, are secondary metabolites produced by Fusarium fungi. Trichothecene mycotoxins cause immune dysfunction, thus leading to diverse responses to infection. The present study evaluated the effect of DON and NIV on nitric oxide (NO) production by RAW264 cells stimulated with lipopolysaccharide (LPS). LPS-induced NO production was reduced in the presence of these toxins. The transcriptional activation and expression of inducible NO synthase (iNOS) by LPS were also repressed by these toxins. DON or NIV inhibited LPS-induced expression of interferon-beta (IFN-beta), which plays an indispensable role in LPS-induced iNOS expression. These results indicate that DON and NIV inhibit the LPS-induced NO and IFN-beta production, which both play an important role for host protection against invading pathogens, and suggests that the inhibition of these factors may be involved in the immunotoxic effects of these mycotoxins. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
  • Yoshida T, Yoshioka Y, Fujimura M, Kayamuro H, Yamashita K, Higashisaka K, Nakanishi R, Morishita Y, Nabeshi H, Yamashita T, Muroi M, Tanamoto K, Nagano K, Abe Y, Kamada H, Kawai Y, Mayumi T, Itoh N, Yoshikawa T, Tsunoda S, Tsutsumi Y
    Biol.Pharm.Bull. 33(5) 780-783 2010年  

書籍等出版物

 15

講演・口頭発表等

 18