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Induction and inhibition of apoptosis: A study of a key immune mechanism.

机译：诱导和抑制细胞凋亡：关键免疫机制的研究。

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摘要

Apoptosis is a controlled process of active cellular self-destruction. Enhancement or blockade of intra- and extra cellular pathways leading to apoptosis is promising concepts for the design of novel experimental and therapeutic strategies. In the current work, we investigated specific aspects of apoptosis in two distinct models: during human cytomegalovirus (HCMV) infection in fibroblasts we have found that in a productive HCMV infection of human fibroblasts, loss of cell viability was not only due to the virus-mediated cell lysis but also apoptosis. Infection is associated with expression of Fas-R---which renders infected cells susceptible to Fas-ligand-mediated apoptosis. While Fas-triggering in infected cultures lead to decreased viral output by elimination of HCMV infected cells, interferon-gamma decreased viral output by inhibition of HCMV life cycle, which resulted in the better preservation of cell viability. In addition to its antiviral activity, IFN-gamma primes HCMV infected cells to the action of Fas-L by up modulation of receptor. This experimental system demonstrates that induction of apoptosis of infected cells, may be an important defense mechanism.;In the second part of this work consequences of apoptosis blockade in hematopoietic progenitor and stem cells were studied. CD34+ cells constitutively express essential caspases (-1, -3 & 8). Fas- and serum starvation-induced apoptosis was inhibited using synthetic peptides suppressing specific caspases involved in the apoptotic transduction pathway. We found that caspase blockade was more effective in preventing Fas-mediated apoptosis than those induced by serum withdrawal. Unlike in lymphoid system, in CD34+ cells, specific inhibitor of caspase-1 showed better anti-apoptotic effect then inhibitors of caspase-3. Although blockade of apoptosis in early hematopoietic progenitor and stein cells, prevented their early loss of viability and clonogenic potential, differentiation and the ultimate exhaustion of the progenitor cells in the culture could not be prevented.;Both experimental systems demonstrate that modulation of apoptotic events can be used as investigational tool. Better understanding of apoptosis and its regulation may facilitate development of novel therapeutic strategies in diseases associated either with excess of or resistance to apoptosis.
机译：凋亡是主动细胞自我毁灭的受控过程。增强或阻断导致细胞凋亡的细胞内和细胞外途径是设计新颖的实验和治疗策略的有希望的概念。在当前的工作中，我们在两种不同的模型中研究了凋亡的特定方面：在成纤维细胞中人类巨细胞病毒（HCMV）感染期间，我们发现在人类成纤维细胞的有效HCMV感染中，细胞活力的丧失不仅是由于病毒-介导的细胞裂解作用以及细胞凋亡。感染与Fas-R-的表达有关-Fas-R-的表达使受感染的细胞易受Fas-配体介导的细胞凋亡。感染培养物中的Fas触发会通过消除HCMV感染的细胞而导致病毒输出降低，而干扰素-γ通过抑制HCMV生命周期而降低了病毒输出，从而更好地保存了细胞活力。除了其抗病毒活性外，IFN-γ还通过上调受体使HCMV感染的细胞起Fas-L的作用。该实验系统证明诱导感染细胞的凋亡可能是重要的防御机制。在本工作的第二部分中，研究了在造血祖细胞和干细胞中凋亡阻断的后果。 CD34 +细胞组成型表达必需的胱天蛋白酶（-1，-3和8）。 Fas和血清饥饿诱导的凋亡被抑制合成凋亡抑制特定caspase参与凋亡通路的肽。我们发现半胱天冬酶阻滞比由血清停药诱导的更能预防Fas介导的细胞凋亡。与淋巴系统不同，在CD34 +细胞中，caspase-1的特异性抑制剂比caspase-3的抑制剂具有更好的抗凋亡作用。尽管阻断早期造血祖细胞和斯坦细胞的凋亡，阻止了它们的早期丧失活力和克隆能力，但无法防止培养物中祖细胞的分化和最终耗尽。这两个实验系统均表明，凋亡事件的调控可以用作研究工具。对细胞凋亡及其调控的更好的理解可以促进新的治疗策略在与细胞凋亡过度或耐药有关的疾病中的发展。

著录项

  • 作者

    Chaudhuri, Aniruddho R.;

  • 作者单位

    University of Nevada, Reno.;

  • 授予单位 University of Nevada, Reno.;
  • 学科 Biology Molecular.;Health Sciences Immunology.;Biology Cell.
  • 学位 Ph.D.
  • 年度 1999
  • 页码 139 p.
  • 总页数 139
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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