Byrnes A A, Ma X, Cuomo P, Park K, Wahl L, Wolf S F, Zhou H, Trinchieri G, Karp C L
Department of Medicine, Johns Hopkins University, Baltimore, USA.
Eur J Immunol. 2001 Jul;31(7):2026-34. doi: 10.1002/1521-4141(200107)31:7<2026::aid-immu2026>3.0.co;2-u.
Therapeutic use of type I IFN (IFN-alpha/beta) has become common. Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell-mediated immunity (CMI), these cellular immune responses either causing injury to the host, lacking sufficient vigor for virus or tumor clearance, or both. In general, therapeutic efficacy is limited. It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood. We characterized the effects of type I IFN on the production of IL-12, the central immunoregulatory cytokine of the CD4(+) T cell arm of CMI. We show that type I IFN are potent inhibitors of IL-12 production by human monocytes/macrophages. The underlying mechanism involves transcriptional inhibition of the IL-12p40 gene, marked by down-regulation of PU.1 binding activity at the upstream Ets site of the IL-12p40 promoter. Type I IFN have previously been shown to be able to substitute for IL-12 in driving IFN-gamma production from T and NK cells. The ability of IFN-alpha/beta to suppress IL-12 production while up-regulating IFN-gamma production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI.
I型干扰素（IFN-α/β）的治疗用途已变得很普遍。许多其针对的不同疾病的特征是细胞介导免疫（CMI）存在致病性异常，这些细胞免疫反应要么对宿主造成损伤，要么缺乏足够的活力来清除病毒或肿瘤，或者两者皆有。一般来说，治疗效果有限。因此，值得注意的是，I型干扰素对CMI的多效性作用仍了解甚少。我们表征了I型干扰素对IL-12产生的影响，IL-12是CMI中CD4(+) T细胞臂的核心免疫调节细胞因子。我们表明，I型干扰素是人类单核细胞/巨噬细胞产生IL-12的有效抑制剂。潜在机制涉及IL-12p40基因的转录抑制，其特征是IL-12p40启动子上游Ets位点的PU.1结合活性下调。先前已表明I型干扰素能够在驱动T细胞和NK细胞产生IFN-γ方面替代IL-12。IFN-α/β抑制IL-12产生而同时上调IFN-γ产生的能力表明，在涉及CMI异常的疾病中使用这些细胞因子存在困难可能有机制基础。
