Kasid A, Director E P, Stovroff M C, Lotze M T, Rosenberg S A
Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
Cancer Res. 1990 Aug 15;50(16):5072-6.
The immune response at the molecular level is characterized by a carefully coordinated interplay of both cytokine production and receptor induction. The regulation of these molecules including the closely related tumor necrosis factors alpha (TNF) and beta (lymphotoxin, LT) is still incompletely understood. We have examined the effects of various cytokines on the expression of TNF and LT mRNA in human peripheral blood mononuclear cells (PBMC). Northern blot analysis with total cellular RNA from mixed populations of PBMC revealed that genes coding for TNF and LT were not spontaneously expressed. Treatment of PBMC with recombinant interleukin (IL)-2 resulted in a high level expression of TNF and LT mRNA. Whereas IL-1 beta was equally effective as IL-2 in inducing both TNF and LT mRNA, granulocyte-macrophage colony-stimulating factor selectively induced only TNF mRNA. Both TNF and LT mRNA were minimally induced by IL-1 alpha, IL-3, interferon (IFN)-alpha, or IFN-gamma. Similarly TNF alone had little effect on induction of TNF and LT mRNA. In conjunction with IL-2, cytokines such as IFN-alpha, IFN-gamma, or TNF did not interfere with IL-2 induction of TNF and LT mRNA. Interestingly, IL-4 in combination with IL-2 inhibited the IL-2-driven induction of TNF and LT mRNA. This inhibitory effect of IL-4 was also observed at the level of TNF and LT protein secretion. Furthermore, IL-4 was also inhibitory of IL-2-mediated induction of Tac mRNA in PBMC. These results extend the interrelationship of cytokine regulation of TNF and LT expression. In particular, they reveal the previously unrecognized function of IL-4 in antagonizing the IL-2 induction of TNF, LT, and Tac mRNA in PBMC.
分子水平的免疫反应以细胞因子产生和受体诱导之间精心协调的相互作用为特征。对包括密切相关的肿瘤坏死因子α（TNF）和β（淋巴毒素，LT）在内的这些分子的调节仍未完全了解。我们研究了各种细胞因子对人外周血单个核细胞（PBMC）中TNF和LT mRNA表达的影响。用来自PBMC混合群体的总细胞RNA进行的Northern印迹分析表明，编码TNF和LT的基因不会自发表达。用重组白细胞介素（IL）-2处理PBMC导致TNF和LT mRNA的高水平表达。而IL-1β在诱导TNF和LT mRNA方面与IL-2同样有效，粒细胞-巨噬细胞集落刺激因子仅选择性诱导TNF mRNA。IL-1α、IL-3、干扰素（IFN）-α或IFN-γ对TNF和LT mRNA的诱导作用最小。同样，单独的TNF对TNF和LT mRNA的诱导作用很小。与IL-2联合使用时，IFN-α、IFN-γ或TNF等细胞因子不会干扰IL-2对TNF和LT mRNA的诱导。有趣的是，IL-4与IL-2联合使用可抑制IL-2驱动的TNF和LT mRNA的诱导。在TNF和LT蛋白分泌水平也观察到了IL-4的这种抑制作用。此外，IL-4还抑制PBMC中IL-2介导的Tac mRNA的诱导。这些结果扩展了细胞因子对TNF和LT表达调节的相互关系。特别是，它们揭示了IL-4在拮抗PBMC中IL-2诱导TNF、LT和Tac mRNA方面以前未被认识的功能。
