An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha.
An inducible autocrine cascade regulates rat hepatocyte proliferation and apoptosis responses to tumor necrosis factor-alpha.
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DOI：
10.1002/hep.22335
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发表时间：
2008-07
期刊：
影响因子：
13.5
通讯作者：
Griffith, Linda G.
中科院分区：
文献类型：
--
作者：
Cosgrove, Benjamin D.;Cheng, Connie;Pritchard, Justin R.;Stolz, Donna B.;Lauffenburger, Douglas A.;Griffith, Linda G.
肿瘤坏死因子-α是一种炎性细胞因子，可诱导肝细胞的上下文依赖性增殖、存活和凋亡反应。肿瘤坏死因子可刺激和增强肝部分切除后生长因子介导的肝细胞增殖和存活，也可在病毒感染过程中与先天免疫反应中的其他炎性细胞因子协同作用，诱导肝细胞凋亡。在其他类型的上皮细胞中，肿瘤坏死因子最近被证明可以刺激转化生长因子-α(转化生长因子-α)和白细胞介素1(IL-1)家族配体的自分泌释放。在这里，我们研究了这些自分泌配体在调节肿瘤坏死因子诱导的原代肝细胞增殖和凋亡中的作用。我们发现，肿瘤坏死因子诱导的肝细胞增殖是由一个可诱导的、耦合的和自拮抗的自分泌级联反应调节的，包括促增殖的转化生长因子-α和IL-1受体拮抗剂(IL-1ra)配体和抗增殖的IL-1α/β配体。此外，联合应用肿瘤坏死因子和转化生长因子-α协同刺激肝细胞增殖；通过抗增殖的IL-1α/β反馈治疗是自限的。我们表明，肿瘤坏死因子有效地诱导腺病毒感染的肝细胞凋亡，其方式类似于通过耦合的转化生长因子-α-IL-1α/β-IL-1ra自分泌级联反应来决定的方式。外源性转化生长因子-α可促进或减少腺病毒载体和肿瘤坏死因子治疗的肝细胞的凋亡，这一双相关系也由自分泌IL-1α/β反馈所介导。我们证明，肿瘤坏死因子诱导的肝细胞增殖和凋亡在体外都是由自拮抗的转化生长因子-α-IL-1、α/β-IL-1ra自分泌级联反应控制的，从而确定了控制肿瘤坏死因子调节的肝细胞表型反应的多个分子靶点，与肝再生和腺病毒基因治疗相关。
Tumor necrosis factor-α (TNF) is an inflammatory cytokine that induces context-dependent proliferation, survival, and apoptosis responses in hepatocytes. TNF stimulates and enhances growth factor-mediated hepatocyte proliferation and survival following partial hepatectomy, but also acts in concert with other inflammatory cytokines of the innate immune response during viral infection to induce apoptosis in hepatocytes. In other epithelial cell types, TNF has recently been shown to stimulate autocrine release of transforming growth factor-α (TGF-α) and interleukin-1 (IL-1) family ligands. Here, we examine the role of these autocrine ligands in modulating TNF-induced proliferation and apoptosis in primary hepatocytes. We show that TNF-induced hepatocyte proliferation is regulated by an inducible, coupled, and self-antagonizing autocrine cascade involving the pro-proliferative TGF-α and IL-1 receptor antagonist (IL-1ra) ligands and antiproliferative IL-1α/β ligands. Moreover, cooperative stimulation of hepatocyte proliferation by combined TNF and TGF-α; treatment is self-limited through antiproliferative autocrine IL-1α/β feedback We show that TNF potently induces apoptosis of adenovirus-infected hepatocytes in a manner similarly determined through the integrated activity of a coupled TGF-α–IL-1α/β–IL-1ra autocrine cascade. Exogenous TGF-α can either enhance or diminish apoptosis in adenoviral vector-treated and TNF-treated hepatocytes, in a biphasic relationship also mediated by autocrine IL-1α/β feedback. We demonstrate that TNF-induced hepatocyte proliferation and apoptosis are both governed by a self-antagonizing TGF-α–IL-1α/β–IL-1ra autocrine cascade in vitro, and thus identify multiple molecular targets for control of TNF-regulated hepatocyte phenotypic responses related to liver regeneration and adenoviral gene therapy.
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影响因子：
4.8
作者：
Berasain, C;García-Trevijano, ER;Avila, MA
通讯作者：
Avila, MA
影响因子：
3.7
作者：
del Castillo, Gaelle;Murillo, Miguel M.;Fabregat, Isabel
通讯作者：
Fabregat, Isabel
DOI：
10.1152/ajpgi.00422.2005
发表时间：
2006-04-01
影响因子：
4.5
作者：
Schwabe, RF;Brenner, DA
通讯作者：
Brenner, DA
DOI：
10.1152/ajpgi.00328.2005
发表时间：
2006-07-01
影响因子：
4.5
作者：
Scheving, LA;Zhang, L;Russell, WE
通讯作者：
Russell, WE
影响因子：
11.2
作者：
Castillo, Josefa;Erroba, Elena;Berasain, Carmen
通讯作者：
Berasain, Carmen