Dickensheets H L, Venkataraman C, Schindler U, Donnelly R P
Division of Cytokine Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10800-5. doi: 10.1073/pnas.96.19.10800.
Interferons (IFNs) inhibit induction by IL-4 of multiple genes in human monocytes. However, the mechanism by which IFNs mediate this inhibition has not been defined. IL-4 activates gene expression by inducing tyrosine phosphorylation, homodimerization, and nuclear translocation of the latent transcription factor, STAT6 (signal transducer and activator of transcription-6). STAT6-responsive elements are characteristically present in the promoters of IL-4-inducible genes. Because STAT6 activation is essential for IL-4-induced gene expression, we examined the ability of type I and type II IFNs to regulate activation of STAT6 by IL-4 in primary human monocytes. Pretreatment of monocytes with IFN-beta or IFN-gamma, but not IL-1, IL-2, macrophage colony-stimulating factor, granulocyte/macrophage colony-stimulating factor, IL-6, or transforming growth factor beta suppressed activation of STAT6 by IL-4. This inhibition was associated with decreased tyrosine phosphorylation and nuclear translocation of STAT6 and was not evident unless the cells were preincubated with IFN for at least 1 hr before IL-4 stimulation. Furthermore, inhibition by IFN could be blocked by cotreatment with actinomycin D and correlated temporally with induction of the JAK/STAT inhibitory gene, SOCS-1. Forced expression of SOCS-1 in a macrophage cell line, RAW264, markedly suppressed trans-activation of an IL-4-inducible reporter as well as IL-6- and IFN-gamma-induced reporter gene activity. These findings demonstrate that IFNs inhibit IL-4-induced activation of STAT6 and STAT6-dependent gene expression, at least in part, by inducing expression of SOCS-1.
干扰素（IFNs）可抑制白细胞介素-4（IL-4）诱导人单核细胞中多个基因的表达。然而，IFNs介导这种抑制作用的机制尚未明确。IL-4通过诱导潜在转录因子STAT6（信号转导及转录激活因子6）的酪氨酸磷酸化、同源二聚化及核转位来激活基因表达。STAT6反应元件典型地存在于IL-4诱导基因的启动子中。由于STAT6激活对于IL-4诱导的基因表达至关重要，我们研究了I型和II型IFNs调节IL-4在原代人单核细胞中激活STAT6的能力。用IFN-β或IFN-γ预处理单核细胞，但不用IL-1、IL-2、巨噬细胞集落刺激因子、粒细胞/巨噬细胞集落刺激因子、IL-6或转化生长因子β，可抑制IL-4对STAT6的激活。这种抑制与STAT6酪氨酸磷酸化及核转位减少有关，且除非细胞在IL-4刺激前用IFN预孵育至少1小时，否则不明显。此外，IFN的抑制作用可被放线菌素D共处理阻断，且在时间上与JAK/STAT抑制基因SOCS-1的诱导相关。在巨噬细胞系RAW264中强制表达SOCS-1，可显著抑制IL-4诱导的报告基因的反式激活以及IL-6和IFN-γ诱导的报告基因活性。这些发现表明，IFNs至少部分地通过诱导SOCS-1的表达来抑制IL-4诱导的STAT6激活及STAT6依赖性基因表达。
