Shnyra A, Brewington R, Alipio A, Amura C, Morrison D C
Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160, USA.
J Immunol. 1998 Apr 15;160(8):3729-36.
We studied the potential role of a cytokine regulatory mechanism(s) in LPS-dependent reprogramming and modulation of TNF-alpha and nitric oxide (NO) responses in mouse peritoneal macrophages. Reciprocal regulation of TNF-alpha and NO production by LPS-primed and LPS-stimulated macrophages was found to be dependent on the presence of soluble secretory products released by the cells during the initial LPS priming interaction. Pretreatment of naive macrophages with different mouse recombinant cytokines such as rIL-10, rIL-12, and rIFN-gamma dose dependently and differentially regulated subsequent LPS-induced production of TNF-alpha, IL-6, and NO by cytokine-primed cells. Analysis of IL-12 and IL-10 levels present in culture supernatants of LPS-primed and LPS-stimulated macrophages revealed a high degree of correlation between the profiles of TNF-alpha and IL-12 as well as NO and IL-10. Furthermore, LPS priming of macrophages in the presence of anti-IL-12-neutralizing mAb attenuated TNF-alpha responses while at the same time up-regulated NO production. In contrast, neutralization of endogenous IL-10 with anti-IL-10 mAb resulted in considerable TNF-alpha response at LPS priming doses under conditions that would otherwise strongly inhibit TNF-alpha production. We also found that the initial LPS priming of naive macrophages differentially and dose dependently regulates expression of mRNAs for IL-10, IL-12, and IFN-gamma in LPS-primed macrophages. Collectively, our data provide experimental support for the hypothesis that a cytokine regulatory network, most probably autocrine, tightly controls the reciprocal modulation of TNF-alpha and NO responses in LPS-primed macrophages.
我们研究了细胞因子调节机制在小鼠腹腔巨噬细胞中脂多糖（LPS）依赖性重编程以及肿瘤坏死因子-α（TNF-α）和一氧化氮（NO）反应调节中的潜在作用。发现LPS预刺激和LPS刺激的巨噬细胞对TNF-α和NO产生的相互调节取决于细胞在初始LPS预刺激相互作用期间释放的可溶性分泌产物的存在。用不同的小鼠重组细胞因子如rIL-10、rIL-12和rIFN-γ对未致敏巨噬细胞进行预处理，可剂量依赖性且差异性地调节随后细胞因子预刺激细胞对LPS诱导的TNF-α、IL-6和NO的产生。对LPS预刺激和LPS刺激的巨噬细胞培养上清液中IL-12和IL-10水平的分析显示，TNF-α和IL-12以及NO和IL-10的表达谱之间存在高度相关性。此外，在抗IL-12中和单克隆抗体存在的情况下对巨噬细胞进行LPS预刺激可减弱TNF-α反应，同时上调NO的产生。相反，用抗IL-10单克隆抗体中和内源性IL-10会在原本会强烈抑制TNF-α产生的条件下，在LPS预刺激剂量时导致相当大的TNF-α反应。我们还发现，对未致敏巨噬细胞进行初始LPS预刺激可差异性地且剂量依赖性地调节LPS预刺激巨噬细胞中IL-10、IL-12和IFN-γ mRNA的表达。总体而言，我们的数据为以下假设提供了实验支持：一个细胞因子调节网络，很可能是自分泌网络，紧密控制着LPS预刺激巨噬细胞中TNF-α和NO反应的相互调节。
