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カスパゼ8は,TNF-α誘発の上皮性ネクロプトーシスと末期性イレチスを調節する
Claudia Günther1, Eva Martini, Nadine Wittkopf
1Department of Medicine 1, Friedrich-Alexander-University, D-91054 Erlangen, Germany.
Nature
|September 17, 2011
まとめ
腸内皮質細胞 (IEC) のカスパース-8欠乏は死滅を引き起こし,マウスのパネス細胞喪失と末期性イレチスを引き起こします. これは,RIP3によって引き起こされるネクロプトーシスが,クローン病に起因する可能性があることを示唆している.
科学分野:
- 胃腸内科と免疫学について
- 細胞生物学と病理学について
背景:
- クローン病は,腸内表 epithelial 機能障害による細菌の転位によって引き起こされる慢性粘膜炎を伴う.
- 皮質細胞死は腸炎の重要な特徴ですが,その調節とホメオスタシスの役割は不明です.
- カスパース-8は,死滅を含む細胞死経路の重要な調節剤です.
研究 の 目的:
- 腸内皮質細胞死とホメオスタシスの調節におけるカスパース-8の役割を調査する.
- カスパゼ8が死滅に関与し,末期性イレチスへの貢献を決定する.
主な方法:
- 腸内表 epithelial 細胞 (Casp8(ΔIEC)) でカスパース-8の条件付きデリションを生成したマウス.
- 分析された腸内ヒストロジー,細胞死マーカー,およびCasp8 (((ΔIEC)) マウスの免疫細胞集団.
- 皮質細胞死と死滅におけるTNF-αとRIP3の役割を調査した.
- ヒトのクローン病組織におけるRIP3発現と死滅を調査した.
主要な成果:
- Casp8 ((ΔIEC) のマウスは,パネス細胞の損失とゴブレット細胞の減少によって特徴づけられる末期性イレチスと大腸炎を自発的に発達させた.
- 皮質細胞死亡の増加,特にネクロプトーシスは,TNF-αによって誘発され,RIP3.3によって媒介されるCasp8 ((ΔIEC) マウスの末端イレウムで観察されました.
- 高濃度のRIP3と増加したネクロプトーシスは,ヒトのクローン病患者の末期性イレウムで発見されました.
結論:
- カスパース-8は,腸内表皮細胞におけるTNF-α誘発性死滅を防ぐことにより,腸内ホメオスタシスの維持に不可欠です.
- カスパース-8の調節不良とそれに続く死滅は,パネス細胞機能障害と末期性イレイチスに寄与する.
- ネクロプトーシス経路,特にRIP3をターゲットにすることで,クローン病の治療戦略を提供することができる.
関連する概念動画
Caspases
Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
The Extrinsic Apoptotic Pathway
The extrinsic apoptotic pathway is initiated when extracellular death-inducing signals, such as specific cytokines, activate the death receptors expressed on the cell surface. The immune cells involved in this pathway are natural killer cells (NK cells) and cytotoxic T-lymphocytes. NK cells are critical in innate immune response, while cytotoxic T-lymphocytes are associated with adaptive immune response. These cells recognize specific receptors expressed on the altered cells and activate...
The Intrinsic Apoptotic Pathway
Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
NF-κB-dependent Signaling Pathway
The transcription factor NF-κB was discovered in 1986 in the lab of Nobel laureate Professor David Baltimore, for its interaction with the immunoglobulin light chain enhancer in B-cells. After more than three decades of study, it is now evident that NF-κB regulates the expression of over 100 genes. Most of these genes play an essential role in the innate and adaptive immune responses as well as the inflammatory responses of animals.
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
NF-κB-dependent Signaling Mechanism
The heterodimer of NF-κB...
Necrosis
Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become anucleated and die, but their...
Cellular Injury V: Apoptosis and Autophagy
Cells respond to damage and stress through highly coordinated processes that decide whether they survive or undergo controlled self-destruction. Two major pathways involved in this regulation are apoptosis, a type of programmed cell death, and autophagy, a survival mechanism that helps cells adapt to adverse conditions.ApoptosisApoptosis removes aged or injured cells to maintain tissue balance. During this process, the cell shrinks, chromatin condenses and fragments, and membrane-bound...
