Elewaut D, DiDonato J A, Kim J M, Truong F, Eckmann L, Kagnoff M F
Laboratory of Mucosal Immunology, Department of Medicine, University of California at San Diego, La Jolla 92093, USA.
J Immunol. 1999 Aug 1;163(3):1457-66.
Human intestinal epithelial cells up-regulate the expression of an inflammatory gene program in response to infection with a spectrum of different strains of enteroinvasive bacteria. The conserved nature of this program suggested that diverse signals, which are activated by enteroinvasive bacteria, can be integrated into a common signaling pathway that activates a set of proinflammatory genes in infected host cells. Human intestinal epithelial cell lines, HT-29, Caco-2, and T84, were infected with invasive bacteria that use different strategies to induce their uptake and have different intracellular localizations (i.e., Salmonella dublin, enteroinvasive Escherichia coli, or Yersinia enterocolitica). Infection with each of these bacteria resulted in the activation of TNF receptor associated factors, two recently described serine kinases, I kappa B kinase (IKK) alpha and IKK beta, and increased NF-kappa B DNA binding activity. This was paralleled by partial degradation of I kappa B alpha and I kappa B epsilon in bacteria-infected Caco-2 cells. Mutant proteins that act as superrepressors of IKK beta and I kappa B alpha inhibited the up-regulated transcription and expression of downstream targets genes of NF-kappa B that are key components of the epithelial inflammatory gene program (i.e., IL-8, growth-related oncogene-alpha, monocyte chemoattractant protein-1, TNF-alpha, cyclooxygenase-2, nitric oxide synthase-2, ICAM-1) activated by those enteroinvasive bacteria. These studies position NF-kappa B as a central regulator of the epithelial cell innate immune response to infection with enteroinvasive bacteria.
人类肠道上皮细胞会对一系列不同菌株的肠侵袭性细菌感染做出反应，上调一种炎症基因程序的表达。该程序的保守性质表明，由肠侵袭性细菌激活的多种信号可以整合到一条共同的信号通路中，该通路在受感染的宿主细胞中激活一组促炎基因。人类肠道上皮细胞系HT - 29、Caco - 2和T84被侵袭性细菌感染，这些细菌采用不同策略诱导自身被摄取且具有不同的细胞内定位（即都柏林沙门氏菌、肠侵袭性大肠杆菌或小肠结肠炎耶尔森菌）。用这些细菌中的每一种进行感染都会导致肿瘤坏死因子受体相关因子、最近描述的两种丝氨酸激酶——IκB激酶（IKK）α和IKKβ的激活，以及核因子κB（NF - κB）DNA结合活性增加。在细菌感染的Caco - 2细胞中，IκBα和IκBε会发生部分降解，这与上述情况同时出现。作为IKKβ和IκBα超级抑制剂的突变蛋白抑制了NF - κB下游靶基因的转录上调和表达，这些靶基因是上皮炎症基因程序的关键组成部分（即白细胞介素 - 8、生长相关癌基因 - α、单核细胞趋化蛋白 - 1、肿瘤坏死因子 - α、环氧化酶 - 2、一氧化氮合酶 - 2、细胞间黏附分子 - 1），这些基因由那些肠侵袭性细菌激活。这些研究将NF - κB定位为上皮细胞对肠侵袭性细菌感染的固有免疫反应的核心调节因子。
