Cytokine-induced beta-cell apoptosis is NO-dependent, mitochondria-mediated and inhibited by BCL-XL.
Cytokine-induced beta-cell apoptosis is NO-dependent, mitochondria-mediated and inhibited by BCL-XL.
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DOI：
10.1111/j.1582-4934.2007.00191.x
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发表时间：
2008-04
影响因子：
5.3
通讯作者：
Samali A
中科院分区：
文献类型：
--
作者：
Holohan C;Szegezdi E;Ritter T;O'Brien T;Samali A
促炎细胞因子被认为是1型糖尿病中β细胞死亡的主要介质，但确切的机制尚不清楚。本研究检测了白细胞介素1β(IL-1β)、干扰素γ和肿瘤坏死因子γ对大鼠胰岛素瘤细胞系(RIN-r)的影响，以探讨细胞因子诱导的α细胞死亡的核心机制。IL-1β和干扰素γ(IL-1β/干扰素γ)联合作用可诱导细胞凋亡。肿瘤坏死因子α既不能诱导β细胞死亡，也不能增强IL-1β、干扰素γ或IL-1β/干扰素γ的作用。IL-1β/干扰素γ的细胞毒作用与诱导型一氧化氮合酶的表达和一氧化氮的产生有关。腺病毒介导的iNOS(AdiNOS)单独表达足以诱导caspase活性和细胞凋亡。广谱caspase抑制剂Boc-D-fmk可阻断IL-1β/干扰素γ诱导的caspase活性，但不能抑制一氧化氮的产生或细胞死亡。然而，一氧化氮合酶抑制剂L-NIO预处理可阻止一氧化氮的产生和caspase活性，并减少细胞凋亡。IL-1β/干扰素γ诱导的细胞凋亡伴随着线粒体膜电位的丧失、细胞色素c的释放和caspase-9、-7、-3酶原的裂解。用Ad-Bclxl转导细胞可以阻断iNOS和细胞因子介导的线粒体改变和随后的细胞凋亡，而不是一氧化氮的下游。我们的结论是，细胞因子诱导的一氧化氮的产生是caspase激活和β细胞死亡的必要条件和充分条件，并已确定Bclxl是一个潜在的抗β细胞凋亡的靶点。
Pro-inflammatory cytokines are implicated as the main mediators of β-cell death during type 1 diabetes but the exact mechanisms remain unknown. This study examined the effects of interleukin-1β (IL-1β), interferon-γ (IFNγ) and tumour necrosis factor α (TNFα) on a rat insulinoma cell line (RIN-r) in order to identify the core mechanism of cytokine-induced β-cell death. Treatment of cells with a combination of IL-1β and IFNγ (IL-1β/IFNγ)induced apoptotic cell death. TNFα neither induced β-cell death nor did it potentiate the effects of IL-1β, IFNγ or IL-1β/IFNγ . The cytotoxic effect of IL-1β/IFNγ was associated with the expression of inducible nitric oxide synthase (iNOS) and production of nitric oxide. Adenoviral-mediated expression of iNOS (AdiNOS) alone was sufficient to induce caspase activity and apoptosis. The broad range caspase inhibitor, Boc-D-fmk, blocked IL-1β/IFNγ -induced caspase activity, but not nitric oxide production nor cell death. However, pre-treatment with L-NIO, a NOS inhibitor, prevented nitric oxide production, caspase activity and reduced apoptosis. IL-1β/IFNγ -induced apoptosis was accompanied by loss of mitochondrial membrane potential, release of cytochrome c and cleavage of pro-caspase-9, -7 and -3. Transduction of cells with Ad-Bcl-XL blocked both iNOS and cytokine-mediated mitochondrial changes and subsequent apoptosis, downstream of nitric oxide. We conclude that cytokine-induced nitric oxide production is both essential and sufficient for caspase activation and β-cell death, and have identified Bcl-XL as a potential target to combatβ-cell apoptosis.
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影响因子：
3.7
作者：
ANKARCRONA, M;DYPBUKT, JM;NICOTERA, P
通讯作者：
NICOTERA, P
影响因子：
4.4
作者：
Chang, I;Cho, NJ;Lee, MS
通讯作者：
Lee, MS
DOI：
10.1016/j.bbrc.2007.03.115
发表时间：
2007-05-25
影响因子：
3.1
作者：
McCabe, Cillian;O'Brien, Timothy
通讯作者：
O'Brien, Timothy
影响因子：
64.8
作者：
Joza, N;Susin, SA;Penninger, JM
通讯作者：
Penninger, JM
DOI：
10.1152/ajprenal.00154.2004
发表时间：
2005-02-01
影响因子：
4.2
作者：
Cilenti, L;Kyriazis, GA;Zervos, AS
通讯作者：
Zervos, AS