Ma Zhendong, Chang Mi Jung, Shah Reesha C, Benveniste Etty N
Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294-0005, USA.
J Leukoc Biol. 2005 Aug;78(2):515-23. doi: 10.1189/jlb.0205112. Epub 2005 May 13.
Interferon-gamma (IFN-gamma) is a pleiotropic cytokine involved in aspects of immune regulation, cell proliferation, and host defense mechanisms directed toward various cancers. Some of the biological functions of IFN-gamma are achieved through inhibition of gene expression, although the mechanisms by which IFN-gamma suppresses gene transcription are poorly understood. Herein, we demonstrate the molecular basis by which IFN-gamma mediates suppression of the matrix metalloproteinase-9 (MMP-9) gene. IFN-gamma-activated signal transducer and activator of transcription-1alpha (STAT-1alpha) suppresses MMP-9 gene transcription, which is dependent on phosphorylation of tyrosine 701 but not phosphorylation of serine 727. The coactivator cyclic AMP response element-binding protein-binding protein (CBP) is an important component of induction of MMP-9 gene transcription. IFN-gamma induces the in vivo association of STAT-1alpha and CBP and decreases the association of CBP to the MMP-9 promoter. IFN-gamma does not influence the stability of CBP nor does IFN-gamma affect chromatin-remodeling events on the MMP-9 promoter. IFN-gamma inhibits the assembly of the MMP-9 transcription complex by suppressing H3/H4 acetylation and inhibiting recruitment of Pol II to the MMP-9 promoter. These findings indicate that IFN-gamma/STAT-1alpha exert their inhibitory effects by affecting multiple aspects of MMP-9 gene transcription.
γ干扰素（IFN-γ）是一种多效性细胞因子，参与免疫调节、细胞增殖以及针对多种癌症的宿主防御机制等多个方面。IFN-γ的一些生物学功能是通过抑制基因表达来实现的，尽管IFN-γ抑制基因转录的机制尚不清楚。在此，我们阐述了IFN-γ介导基质金属蛋白酶-9（MMP-9）基因抑制的分子基础。IFN-γ激活的信号转导和转录激活因子1α（STAT-1α）抑制MMP-9基因转录，这依赖于酪氨酸701的磷酸化而非丝氨酸727的磷酸化。共激活因子环磷酸腺苷反应元件结合蛋白结合蛋白（CBP）是MMP-9基因转录诱导的重要组成部分。IFN-γ诱导STAT-1α与CBP在体内的结合，并减少CBP与MMP-9启动子的结合。IFN-γ不影响CBP的稳定性，也不影响MMP-9启动子上的染色质重塑事件。IFN-γ通过抑制H3/H4乙酰化和抑制RNA聚合酶II募集到MMP-9启动子来抑制MMP-9转录复合物的组装。这些发现表明，IFN-γ/STAT-1α通过影响MMP-9基因转录的多个方面发挥其抑制作用。
