Doukas J, Pober J S
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115.
J Immunol. 1990 Sep 15;145(6):1727-33.
Previous studies have established that different cytokines induce distinct patterns of activation in cultured endothelial cells (EC). Treatment of EC with either TNF or IL-1 causes transient induction of endothelial leukocyte adhesion molecule-1 (ELAM-1) and a sustained increase in intercellular adhesion molecule-1 (ICAM-1) expression. TNF but not IL-1 also increases class I MHC Ag expression. IFN-gamma, which by itself increases EC class I MHC and ICAM-1 but does not induce ELAM-1 expression, has been found to act synergistically with TNF to increase class I expression. In our study, we have further examined IFN-gamma effects on both TNF and IL-1 beta responses. In contrast to IFN-gamma plus TNF cotreatment, IFN-gamma up-regulation of class I MHC molecules is not augmented by cotreatment with IL-1 beta. IFN-gamma plus TNF cotreatment synergistically increases ICAM-1 expression by 24 h of cotreatment, whereas IFN-gamma plus IL-1 beta cotreated EC show at most additive increases. IFN-gamma increases TNF-induced ELAM-1 expression such that a greater number of EC express ELAM-1 at both 4 and 24 h in the presence of IFN-gamma plus TNF compared to cultures treated with TNF alone, although the maximal level of surface expression on individual cells is not increased. Inasmuch as these times represent pre- and post-peak expression time (6 h), respectively, IFN-gamma appears both to accelerate and to prolong transient ELAM-1 expression. Although similar interactions are seen with IL-1 beta, IFN-gamma has a consistently greater effect on TNF-induced compared to IL-1-induced ELAM-1 expression. We next explored the possible mechanism(s) of the synergy between IFN-gamma and TNF. IFN-gamma and TNF do not cooperatively enhance total protein synthesis. Unexpectedly, IFN-gamma and IL-1 beta combine to depress protein synthesis, which may contribute to the failure of these cytokines to positively interact. IFN-gamma and TNF cooperatively increase ELAM-1 mRNA at 6 h and ICAM-1 mRNA at both 6 and 24 h, whereas IFN-gamma and IL-1 show markedly less cooperative augmentation of these transcripts. We conclude that IFN-gamma enhances TNF-induced EC activation by selectively and synergistically increasing synthesis of specific surface molecules, whereas IL-1-induced EC activation is largely unaffected by IFN-gamma.
以往的研究表明，不同的细胞因子可诱导培养的内皮细胞（EC）产生不同的激活模式。用肿瘤坏死因子（TNF）或白细胞介素-1（IL-1）处理内皮细胞会导致内皮白细胞黏附分子-1（ELAM-1）的短暂诱导以及细胞间黏附分子-1（ICAM-1）表达的持续增加。TNF可增加I类主要组织相容性复合体（MHC）抗原的表达，而IL-1则无此作用。干扰素-γ（IFN-γ）本身可增加内皮细胞I类MHC和ICAM-1的表达，但不诱导ELAM-1的表达，已发现它可与TNF协同作用以增加I类表达。在我们的研究中，我们进一步研究了IFN-γ对TNF和IL-1β反应的影响。与IFN-γ加TNF联合处理不同，IFN-γ对I类MHC分子的上调作用不会因与IL-1β联合处理而增强。IFN-γ加TNF联合处理在24小时的联合处理中协同增加ICAM-1的表达，而IFN-γ加IL-1β联合处理的内皮细胞最多显示相加性增加。IFN-γ增加TNF诱导的ELAM-1表达，因此与单独用TNF处理的培养物相比，在存在IFN-γ加TNF的情况下，在4小时和24小时时有更多的内皮细胞表达ELAM-1，尽管单个细胞表面表达的最大水平没有增加。由于这些时间分别代表峰值前和峰值后表达时间（6小时），IFN-γ似乎既能加速又能延长ELAM-1的短暂表达。尽管在IL-1β处理中也观察到类似的相互作用，但与IL-1诱导的ELAM-1表达相比，IFN-γ对TNF诱导的ELAM-1表达始终具有更大的影响。接下来，我们探讨了IFN-γ与TNF之间协同作用的可能机制。IFN-γ和TNF不会协同增强总蛋白合成。出乎意料的是，IFN-γ和IL-1β联合作用会抑制蛋白合成，这可能导致这些细胞因子无法产生正向相互作用。IFN-γ和TNF在6小时协同增加ELAM-1 mRNA，在6小时和24小时协同增加ICAM-1 mRNA，而IFN-γ和IL-1对这些转录本的协同增强作用明显较小。我们得出结论，IFN-γ通过选择性地和协同地增加特定表面分子的合成来增强TNF诱导的内皮细胞激活，而IL-1诱导的内皮细胞激活在很大程度上不受IFN-γ的影响。
