Pylaeva Ekaterina, Lang Stephan, Jablonska Jadwiga
Translational Oncology, Department of Otolaryngology, University Hospital Essen , Essen , Germany.
Front Immunol. 2016 Dec 21;7:629. doi: 10.3389/fimmu.2016.00629. eCollection 2016.
Type I interferons (IFNs) were first characterized in the process of viral interference. However, since then, IFNs are found to be involved in a wide range of biological processes. In the mouse, type I IFNs comprise a large family of cytokines. At least 12 IFN-α and one IFN-β can be found and they all signal through the same receptor (IFNAR). A hierarchy of expression has been established for type I IFNs, where IFN-β is induced first and it activates in a paracrine and autocrine fashion a cascade of other type I IFNs. Besides its importance in the induction of the IFN cascade, IFN-β is also constitutively expressed in low amounts under normal non-inflammatory conditions, thus facilitating "primed" state of the immune system. In the context of cancer, type I IFNs show strong antitumor function as they play a key role in mounting antitumor immune responses through the modulation of neutrophil differentiation, activation, and migration. Owing to their plasticity, neutrophils play diverse roles during cancer development and metastasis since they possess both tumor-promoting (N2) and tumor-limiting (N1) properties. Notably, the differentiation into antitumor phenotype is strongly supported by type I IFNs. It could also be shown that these cytokines are critical for the suppression of neutrophil migration into tumor and metastasis site by regulating chemokine receptors, e.g., CXCR2 on these cells and by influencing their longevity. Type I IFNs limit the life span of neutrophils by influencing both, the extrinsic as well as the intrinsic apoptosis pathways. Such antitumor neutrophils efficiently suppress the pro-angiogenic factors expression, e.g., vascular endothelial growth factor and matrix metallopeptidase 9. This in turn restricts tumor vascularization and growth. Thus, type I IFNs appear to be the part of the natural tumor surveillance mechanism. Here we provide an up to date review of how type I IFNs influence the pro- and antitumor properties of neutrophils. Understanding these mechanisms is particularly important from a therapeutic point of view.
I型干扰素（IFNs）最初是在病毒干扰过程中被鉴定出来的。然而，从那时起，人们发现IFNs参与了广泛的生物学过程。在小鼠中，I型IFNs构成了一个庞大的细胞因子家族。可以发现至少12种IFN-α和1种IFN-β，它们都通过同一受体（IFNAR）发出信号。I型IFNs已建立了表达层次结构，其中IFN-β首先被诱导，并以旁分泌和自分泌方式激活一系列其他I型IFNs。除了在诱导IFN级联反应中的重要性外，IFN-β在正常非炎症条件下也以低水平组成性表达，从而促进免疫系统的“预激发”状态。在癌症背景下，I型IFNs表现出强大的抗肿瘤功能，因为它们在通过调节中性粒细胞的分化、激活和迁移来启动抗肿瘤免疫反应中起关键作用。由于其可塑性，中性粒细胞在癌症发展和转移过程中发挥着多种作用，因为它们同时具有促肿瘤（N2）和抑肿瘤（N1）特性。值得注意的是，I型IFNs强烈支持向抗肿瘤表型的分化。还可以证明，这些细胞因子通过调节趋化因子受体，例如这些细胞上的CXCR2，并通过影响它们的寿命，对于抑制中性粒细胞向肿瘤和转移部位的迁移至关重要。I型IFNs通过影响外在和内在凋亡途径来限制中性粒细胞的寿命。这种抗肿瘤中性粒细胞有效地抑制促血管生成因子的表达，例如血管内皮生长因子和基质金属肽酶9。这反过来限制了肿瘤血管生成和生长。因此，I型IFNs似乎是天然肿瘤监测机制的一部分。在这里，我们提供了一篇关于I型IFNs如何影响中性粒细胞的促肿瘤和抗肿瘤特性的最新综述。从治疗角度理解这些机制尤为重要。
