Salzman A L, Eaves-Pyles T, Linn S C, Denenberg A G, Szabó C
Division of Critical Care, Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Gastroenterology. 1998 Jan;114(1):93-102. doi: 10.1016/s0016-5085(98)70637-7.
BACKGROUND & AIMS: Enterocytes play a major role in the mucosa as a source of proinflammatory cytokines and cytotoxins. We tested the hypothesis that bacteria induce expression of the inducible nitric oxide synthase (iNOS) in cultured human enterocytes.
DLD-1 and Caco-2BBe cell monolayers exposed to Salmonella dublin were analyzed for iNOS up-regulation and nitric oxide production (NOx) in the presence of various proinflammatory cytokines.
S. dublin augmented NOx in interferon gamma (IFN-gamma)-primed cells but had no independent effect on iNOS expression. S. dublin-induced NOx was not mediated by endotoxin and was augmented by an enteroinvasive phenotype. In DLD-1 cells, S. dublin-mediated NOx was blocked by inhibitors of nuclear factor kappa B (NF-kappa B) and tyrosine kinase activation and was steroid resistant. Cis-acting elements in the human iNOS promoter responsive to endotoxin and S. dublin stimulation of IFN-gamma-treated DLD-1 cells were identified between 10.9 and 8.7 kilobases upstream of the transcription initiation site.
S. dublin alters the regulation of iNOS messenger RNA in IFN-gamma-treated intestinal epithelial cells via a steroid-resistant pathway involving NF-kappa B and tyrosine kinase activity. Because bacterial interaction with cytokine-primed epithelial cells induces the synthesis of NO, an endogenous antimicrobial agent, these findings may have implications for the regulation of mucosal immunity.
肠上皮细胞作为促炎细胞因子和细胞毒素的来源，在黏膜中发挥着主要作用。我们检验了细菌可诱导培养的人肠上皮细胞中诱导型一氧化氮合酶（iNOS）表达的假说。
分析暴露于都柏林沙门氏菌的DLD-1和Caco-2BBe细胞单层在各种促炎细胞因子存在时iNOS的上调情况及一氧化氮生成（NOx）。
都柏林沙门氏菌在经γ干扰素（IFN-γ）预处理的细胞中增强了NOx，但对iNOS表达无独立影响。都柏林沙门氏菌诱导的NOx不是由内毒素介导的，且因肠侵袭表型而增强。在DLD-1细胞中，都柏林沙门氏菌介导的NOx被核因子κB（NF-κB）抑制剂和酪氨酸激酶激活抑制剂阻断，且对类固醇耐药。在转录起始位点上游10.9至8.7千碱基之间鉴定出了人iNOS启动子中对内毒素和都柏林沙门氏菌刺激IFN-γ处理的DLD-1细胞有反应的顺式作用元件。
都柏林沙门氏菌通过涉及NF-κB和酪氨酸激酶活性的类固醇耐药途径改变经IFN-γ处理的肠上皮细胞中iNOS信使核糖核酸的调控。由于细菌与经细胞因子预处理的上皮细胞相互作用会诱导内源性抗菌剂一氧化氮的合成，这些发现可能对黏膜免疫的调控有影响。
