Innate immunity and inflammation: A transcriptional paradigm
Innate immunity and inflammation: A transcriptional paradigm
复制标题
DOI：
10.1385/ir:23:2-3:099
复制
发表时间：
2001-01-01
影响因子：
4.4
通讯作者：
Hawiger, J
中科院分区：
文献类型：
--
作者：
Hawiger, J
先天免疫反应和炎症过程是交织在一起的。对细菌脂多糖或超抗原的过度和持续的细胞因子产生是全身性炎症反应(IR)的一个标志，这可能危及生命。这些细菌产物的传播诱导了一波又一波的促炎细胞因子，导致血管损伤和多器官功能障碍。内毒素和超抗原分别在单核巨噬细胞和T细胞中诱导信号传导至细胞核。这些信号通路是由核因子-kappaB和其他应激反应转录因子(SRTF)介导的，它们在基因表达的重新编程中起着关键作用。核因子-kappaB的核进口允许100多种绅士转录激活，这些绅士编码炎症和免疫反应的介质。我们开发了一种新的方法，通过单核细胞、巨噬细胞、T淋巴细胞和血管内皮细胞的细胞通透性多肽转导来阻断核转录因子-kappaB的核输入。引人注目的是，一种细胞通透性多肽可以对抗核因子-kappaB和其他SRTF的核输入，抑制致死剂量的内毒素攻击小鼠体内致炎细胞因子(肿瘤坏死因子α和干扰素γ)的系统产生，并将小鼠的存活率提高至少90%。因此，全身炎症反应严重依赖于由核因子-kappaB和其他SRTF控制的细胞因子基因的转录激活。
The innate immune response and the process of inflammation are interwoven. Excessive and continuing cytokine production in response to bacterial lipopolysacharides (LPS) or superantigens is a hallmark of the systemic inflammatory response (IR), which can be life-threatening. Dissemination of these bacterial products induces waves of proinflammatory cytokines that cause vascular injury and multiple organ dysfunction. Both LPS and superantigens induce signaling to the nucleus in mononuclear phagocytes and T cells, respectively. These signaling pathways are mediated by NF-kappaB and other stress-responsive transcription factors (SRTFs), which play a critical role in reprogramming gene expression. The nuclear import of NF-kappaB allows transcriptional activation of over 100 gents that encode mediators of inflammatory and immune responses. We have developed a novel method to block nuclear import of NF-kappaB through cell-permeable peptide transduction in monocytes, macrophages, T lymphocytes, and endothelial cells. Strikingly, a cell-permeable peptide that antagonizes nuclear import of NF-kappaB and other SRTFs, suppressed the systemic production of proinflammatory cytokines: (TNF alpha and interferon gamma) in mice challenged with a lethal dose of LPS, and increased their survival by at least 90%. Thus, systemic inflammatory responses are critically dependent on the transcriptional activation of cytokine genes that are controlled by NF-kappaB and other SRTFs.