A dual mechanism of immunosuppression by FK-506. Differential suppression of IL-4 and IL-10 levels in T helper 2 cells.
A dual mechanism of immunosuppression by FK-506. Differential suppression of IL-4 and IL-10 levels in T helper 2 cells.
复制标题
FK-506 的双重免疫抑制机制。
DOI：
10.1097/00007890-199310000-00038
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发表时间：
1993
期刊：
影响因子：
6.2
通讯作者：
Tweardy,DJ
中科院分区：
文献类型：
--
作者：
Wang,SC;Morel,PA;Wang,Q;Jordan,ML;Simmons,RL;Tweardy,DJ
已知FK-506可以抑制几种编码细胞因子的基因的转录（例如，IL-2, IFN-[γ]），这些基因被认为在同种异体移植物反应中起重要作用。这种对细胞因子基因转录和蛋白质产生的普遍抑制被认为是FK-506抑制免疫反应的主要机制。我们研究了FK-506对分化的小鼠th2细胞系细胞因子的抑制模式。经FK-506处理的Th2细胞上清液显示IL-4有明显抑制，但IL-10水平仅有中度抑制。为了确定这种对IL-4和IL-10的差异效应是否也可以在mRNA水平上观察到，从(1)培养基、(2)Con A （2 [μ] g/ml）、(3)FK-506 （50 ng/ml）或(4)Con A+ FK-506处理的细胞中分离细胞总RNA。采用逆转录聚合酶链反应和northern blot检测IL-4和IL-10 mRNA。与蛋白水平的结果相似，FK-506显著抑制稳态IL-4 mRNA水平，但对稳态IL-10 mRNA水平的影响较小。此外，FK-506完全抑制Con a诱导的IL-4 mRNA上调，但仅轻微抑制Con a诱导的IL-10 mRNA上调。IL-10（细胞因子合成抑制因子）是一种具有免疫抑制特性的细胞因子，其本身可抑制小鼠辅助细胞产生IL-2和IFN-[γ]。IL-10也下调MHC II的表达和单核细胞的抗原呈递。因此，FK-506对免疫刺激细胞因子如IL-2、IL-4和IFN-[γ] mRNA水平的差异抑制能力高于免疫抑制细胞因子IL-10的mRNA水平，这表明FK-506在体内有效的免疫抑制可能是这两种作用的结合。
FK-506 is known to suppress the transcription of several genes encoding cytokines (eg, IL-2, IFN-[gamma]) thought to play an important role in the allograft response. This general inhibition of cytokine gene transcription and protein production was previously thought to be the main mechanism by which FK-506 suppressed the immune response. We have studied the pattern of cytokine suppression caused by FK-506 in differentiated murine Th 2 cell lines. Supernatants from Th2 cells treated with FK-506 showed marked suppression of IL-4 but only moderate suppression of IL-10 levels. To determine whether this differential effect on IL-4 and IL-10 could also be seen at the mRNA level, total cellular RNA was isolated from cells treated with (1) media,(2) Con A (2 [mu] g/ml),(3) FK-506 (50 ng/ml), or (4) Con A+ FK-506. Reverse transcription-polymerase chain reaction and northern blot analysis were used to measure IL-4 and IL-10 mRNA. Similar to results at the protein level, FK-506 suppressed steady state levels of IL-4 mRNA markedly but had a lesser effect on steady state levels of IL-10 mRNA. Furthermore, FK-506 completely abrogated Con A-induced upregulation of IL-4 mRNA, but only slightly suppressed Con A-induced upregulation of IL-10 mRNA. IL-10 (cytokine synthesis inhibitory factor) is a cytokine with immunosuppressive properties that itself inhibits the production of IL-2 and IFN-[gamma] by murine helper cells. IL-10 also downregulates MHC II expression and antigen presentation by monocytes. Therefore, the ability of FK-506 to differentially suppress the mRNA levels of immunostimulatory cytokines such as IL-2, IL-4, and IFN-[gamma] more than the mRNA levels of the immunosuppressive cytokine IL-10 suggests that the effective immunosuppression seen in vivo with FK-506 may be a combination of these 2 effects.