卡斯巴-1处理IFN-诱导因子,并调节LPS诱导的IFN-产生
T Ghayur1, S Banerjee, M Hugunin
1BASF Bioresearch Corporation, Worcester, Massachusetts 01605-4314, USA. ghayur@biovax.dnet.basf-ag.de
Nature
|April 10, 1997
概括
介素-18 (IGIF) 的成熟需要酶-1,一种蛋白酶也参与IL-1β的产生. 卡斯巴酶-1抑制或缺乏会减少炎症性细胞因子的产生,这表明新的抗炎药物点.
科学领域:
- 免疫学 免疫学 免疫学
- 分子生物学分子生物学
- 细胞因子信号传递
背景情况:
- 干扰素-诱导因子 (IGIF,也称为介乐金-18或IL-18) 是一种诱导干扰素- (IFN-γ) 生产的细胞因子.
- IGIF以非活性前体 (proIGIF) 的形式合成,并且需要蛋白质分解处理才能激活.
- 互白素-1β (IL-1β) 生产还涉及前体被酶-1分裂.
研究的目的:
- 研究caspase-1在proIGIF成熟中的作用.
- 确定卡斯帕-1是否参与IGIF和IFN-γ的生理生产.
- 探索caspase-1作为炎症疾病治疗点的潜力.
主要方法:
- 在体外处理试验中使用净化proIGIF和proIL-1β与caspase-1进行分析.
- 用脂聚糖 (LPS) 刺激的人类单核细胞中caspase-1活性的抑制.
- 在用LPS刺激的caspase-1缺乏的小鼠中评估IFN-γ的产生.
主要成果:
- 在体外,Caspase-1有效地处理了proIGIF和proIL-1β.
- 选择性酶-1抑制剂阻断了人类细胞中LPS诱导的IL-1β和IFN-γ的产生.
- 卡斯巴-1缺乏的小鼠显示LPS诱导的IFN-γ产生受损.
结论:
- 卡斯巴-1在IGIF (IL-18) 的生理成熟中起着至关重要的作用.
- 卡斯帕酶-1对于产生多种促炎性细胞因子至关重要,包括IL-1β和IGIF.
- 用特定的抑制剂向caspase-1为开发新型抗炎疗法提供了潜在的战略.
相关概念视频
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...
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...
Amplifying Signals via Enzymatic Cascade
When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze the...
The JAK-STAT Signaling Pathway
Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as SH2...


