研究者詳細 - 久原　真

論文 - 久原　真

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Caspase-11 Mediates Inflammatory Dopaminergic Cell Death in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson's Disease

Tsuyoshi Furuya, Hideki Hayakawa, Masanori Yamada, Kenji Yoshimi, Shin Hisahara, Masayuki Miura, Yoshikuni Mizuno, Hideki Mochizuki

Journal of Neuroscience ( 8 ) 24 ( 8 ) 1865 - 1872 2004年02月 [査読有り]

The present study was designed to elucidate the inflammatory and apoptotic mechanisms of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in a model of Parkinson's disease. Our results showed that mutant mice lacking the caspase-11 gene were significantly more resistant to the effects of acute treatment with MPTP than their wild-type mice. Thus, the neurotoxicity of MPTP seems to be mediated by the induction of both mitochondrial dysfunction and free radical generation. Previously, we showed that overexpression of the Apaf-1 dominant-negative inhibitor inhibited the mitochondrial apoptotic cascade in chronic MPTP treatment but not in acute MPTP treatment. The present results indicate that MPTP neurotoxicity may be mediated via activation of the caspase-11 cascade and inflammatory cascade, as well as the mitochondrial apoptotic cascade.

DOI PubMed

Caspases determine the vulnerability of oligodendrocytes in the ischemic brain

M Shibata, S Hisahara, H Hara, T Yamawaki, Y Fukuuchi, JY Yuan, H Okano, M Miura

JOURNAL OF CLINICAL INVESTIGATION ( AMER SOC CLINICAL INVESTIGATION INC ) 106 ( 5 ) 643 - 653 2000年09月 [査読有り]

Although oligodendrocytes (OLGs) are thought to be vulnerable to hypoxia and ischemia, little is known about the detailed mechanism by which these insults induce OLG death. From the clinical viewpoint, it is imperative to protect OLGs as well as neurons against ischemic injury (stroke), because they are the only myelin-forming cells of the central nervous system. Using the Cre/loxP system, we have established a transgenic mouse line that selectively expresses p35, a broad-spectrum caspase inhibitor, in OLGs. After hypoxia, cultured OLGs derived from wild-type mice exhibited significant upregulation of caspase-11 and substantial activation of caspase-3, which led to cell loss. Expression of p35 or elimination of caspase-11 suppressed the caspase-3 activation and conferred significant protection against hypoxic injury. Expression of p35 in OLGs in vivo resulted in significant protection from ischemia-induced cell injury, thus indicating that caspases are involved in the ischemia-induced cell death of OLGs. Furthermore, the induction of caspase-11 was evident in the ischemic brains of wild-type mice, and OLGs exhibited resistance to brain ischemia in mice deficient in caspase-11, suggesting that caspase-11 is critically implicated in the mechanism(s) underlying ischemia-induced OLG death. Caspases may therefore offer a good therapeutic target for reducing ischemia-induced damage to OLGs.

Nerve growth factor protects oligodendrocytes from tumor necrosis factor-alpha-induced injury through Akt-mediated signaling mechanisms

R Takano, S Hisahara, K Namikawa, H Kiyama, H Okano, M Miura

JOURNAL OF BIOLOGICAL CHEMISTRY ( AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC ) 275 ( 21 ) 16360 - 16365 2000年05月 [査読有り]

Tumor necrosis factor-alpha is thought to be one of the most important inflammatory cytokines associated with the demyelinating disease multiple sclerosis, We determined whether neurotrophins could protect oligodendrocytes from tumor necrosis factor-alpha-mediated cytotoxicity. Among the neurotrophins tested, nerve growth factor was most effective at preventing cell death. Nerve growth factor also prevented the tumor necrosis factor-induced loss of mitochondrial membrane potential. Overexpression of constitutively active Akt, a downstream target of phosphatidylinositol 3-kinase, but not of constitutively active MEK, protected oligodendrocytes from tumor necrosis factor-induced injury. Moreover, overexpression of dominant-negative Akt negated the protective effects of nerve growth factor on tumor necrosis factor-mediated oligodendrocyte cytotoxicity. These findings indicate that the Akt pathway is crucial in nerve growth factor-mediated oligodendrocyte protection.

Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

S Hisahara, R Takano, S Shoji, H Okano, M Miura

ADVANCES IN RESEARCH ON NEURODEGENERATION, VOL 7 ( SPRINGER-VERLAG WIEN ) 7 135 - 142 2000年 [査読有り]

Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, OLG cell deaths have been observed in demyelinating diseases including multiple sclerosis (MS). Clinical observations and in vitro cell culture studies have suggested that cytokines mediate OLG cell damage in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The administration of TNF-alpha to primary cultures of OLGs induced DNA fragmentation, and significantly decreased the number of live OLGs. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-like proteases) enhanced the survival of TNF-a treated OLGs better than Ac-DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.

Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

S Hisahara, R Takano, S Shoji, H Okano, M Miura

JOURNAL OF NEURAL TRANSMISSION-SUPPLEMENT ( SPRINGER-VERLAG ) ( 58 ) 135 - 142 2000年 [査読有り]

Oligodendrocytes are myelin forming cells in mammalian central nervous system. About 50% of oligodendrocytes (OLGs) undergo cell death in normal development. In addition, OLG cell deaths have been observed in demyelinating diseases including multiple sclerosis (MS). Clinical observations and in vitro cell culture studies have suggested that cytokines mediate OLG cell damage in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The administration of TNF-alpha to primary cultures of OLGs induced DNA fragmentation, and significantly decreased the number of live OLGs. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-like proteases) enhanced the survival of TNF-alpha treated OLGs better than Ac-DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from caspase-11-deficient mice are partially resistant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.

Conditional expression of anti-apoptotic protein p35 by Cre-mediated DNA recombination in cardiomyocytes from loxP-p35-transgenic mice

T. Araki, M. Shibata, R. Takano, S. Hisahara, S. I. Imamura, Y. Fukuuchi, T. Saruta, H. Okano, M. Miura

Cell Death and Differentiation ( Nature Publishing Group ) 7 ( 5 ) 485 - 492 2000年 [査読有り]

p35, a viral inhibitor of caspase, prevents cell death induced by various stimuli. We established an experimental system to study the involvement of caspases in cell death, using primary cultured cells from p35 transgenic mice in which the p35 open reading frame (ORF) had been disrupted by the insertion of a DNA segment flanked by loxP sites, the Cre recognition sites. In this system, p35 expression can be initiated by Cre recombinase. Cardiomyocytes, which are highly sensitive to hypoxic stress, were infected with an adenovirus carrying the cre gene (AxCANCre). Expression of p35 by infection with AxCANCre resulted in inhibition of caspase-3 activation and resistance to hypoxia-induced cell death. Hypoxia-induced cytochrome c release was also attenuated in p35-expressing cardiomyocytes. Our transgenic mice can be used as an experimental model for studying the involvement of caspases in various degenerative diseases as well as programmed cell death both in vitro and in vivo.

DOI PubMed

Proapoptotic activity of Caenorhabditis elegans CED-4 protein in Drosophila: Implicated mechanisms for caspase activation

H Kanuka, S Hisahara, K Sawamoto, S Shoji, H Okano, M Miura

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA ( NATL ACAD SCIENCES ) 96 ( 1 ) 145 - 150 1999年01月 [査読有り]

CED-4 protein plays an important role in the induction of programmed cell death in Caenorhabditis elegans through the activation of caspases. However, the precise mechanisms by which it activates caspases remain unknown. To investigate the conservation of CED-4 function in evolution, transgenic Drosophila lines that express CED-4 in the compound eye were generated. Ectopic expression of CED-4 in the eyes induced massive apoptotic cell death through caspase activation. An ATP-binding site (P-loop) mutation in CED-4 (K165R) causes a loss of function in its ability to activate Drosophila caspase, and an ATPase inhibitor blocks the CED-4-dependent caspase activity in Drosophila S2 cells. Immunoprecipitation analysis showed that both CED-4 and CED-4 (K165R) bind directly to Drosophila caspase drICE, and the overexpression of CED-4 (K165R) inhibits CED-4-, ecdysone-, or cycloheximide-dependent caspase activation in S2 cells. Furthermore, CED-4 (K165R) partially prevented cell death induced by CED-4 in Drosophila compound eyes. Thus, CED-4 function is evolutionarily conserved in Drosophila, and the molecular mechanisms by which CED-4 activates caspases might require ATP binding and direct interaction with the caspases.

DOI PubMed CiNii

Involvement of caspases in cytotoxic cytokine-mediated oligodendrocyte cell death

M Miura, S Hisahara, R Takano, S Shoji, H Okano

PROTOPLASMA ( SPRINGER-VERLAG WIEN ) 206 ( 4 ) 219 - 223 1999年 [査読有り]

Oligodendrocytes are myelin-forming cells in the mammalian central nervous system. About 50% of oligodendrocytes undergo cell death in normal development. In addition, massive oligodendrocyte cell death has been observed in multiple sclerosis. Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes in multiple sclerosis. The addition of TNF-alpha to primary cultures of oligodendrocytes significantly decreased the number of live cells in 72 h. DNA fragmentation was detected in TNF-treated oligodendrocytes at 36 h by TUNEL assay. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 [ICE]-like proteases) as well as Ac-DEVD-CHO (a specific inhibitor of caspase-3[CPP32]-like proteases) enhanced the survival of oligodendrocytes treated with TNF-alpha, indicating that caspase-1- and the caspase-3-mediated cell-death pathways are activated in TNF-induced oligodendrocyte cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from CASP-11-deficient mice are partially resistant to TNF-induced oligodendrocyte cell death. Our results suggest that the inhibition of caspases may be a novel approach to treat multiple sclerosis.

Involvement of caspases in the TNF-alpha-mediated oligodendrocyte cell death

S Hisahara, S Shoji, H Okano, M Miura

NEURAL DEVELOPMENT-BOOK ( SPRINGER-VERLAG TOKYO ) 2 350 - 354 1999年 [査読有り]

Oligodendrocytes (OLGs) are selectively destroyed in chronically demyelinated multiple sclerosis (MS) lesions. Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of OLGs in MS. The addition of TNF-alpha to primary cultures of mouse OLGs, which express caspase-1 and caspase-3 bur not caspase-2, significantly decreased the number of live OLGs in 72 h. DNA fragmentation was detected in TNF-treated OLGs at 36h with TUNEL staining. Z-Asp-CH(2)-DCB, a broad inhibitor of the caspase family, prevented TNF-induced cell death of OLGs. Furthermore, Ac-YVAD-CHO (a specific inhibitor of caspase-1-like proteases) as well, as Ac-DEVD-CHO (a specific inhibitor of caspase-3-lilte proteases) enhanced the survival of OLGs treated with TNF-alpha, indicating that the caspase-1- and the caspase-3-mediated cell-death pathways are involved in TNF-induced OLG cell death. Our results suggest that inhibition of caspases may be a novel approach to treat MS.

Execution mechanisms of programmed cell death by caspase (ICE/CED3) family proteases

M Miura, S Hisahara, T Araki, H Okano

HEART AND VESSELS ( SPRINGER VERLAG ) 66 - 70 1997年 [査読有り]

Molecular genetic study of Caenorhabditis elegans revealed the cell death-executing gene ced-3 Structural and functional similarities between CED-3 and mammalian ICE family (caspase) gene products provide the evidence that mammalian caspases are common mediators in executing programmed cell death. These findings suggest that the execution mechanisms of cell death by caspase family protease may be evolutionarily conserved from worms to mammals. This report summarizes the unique properties of caspases in apoptosis.

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