Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People's Republic of China.
J Immunol. 2013 Jun 1;190(11):5882-93. doi: 10.4049/jimmunol.1201881. Epub 2013 Apr 29.
Neutrophils are known to have antitumor potential. However, in recent years the tumor-promoting effect of neutrophils has been well demonstrated. So far, it remains unclear what causes the conversion of neutrophil function from tumor suppressive to tumor promoting. In this article, we report that the conversion of murine neutrophil function occurs in bone marrow, and that IL-6 cooperation with G-CSF is required for this conversion. IL-6 cooperated with G-CSF to modulate neutrophils in bone marrow, altering the activation potential of signaling pathways in neutrophils, especially that of STAT3. Costimulation with G-CSF and IL-6 induced a higher level of phospho-STAT3 in neutrophils, which was further increased by upregulation of STAT3 expression in neutrophils owing to downregulation of IFN-β expression in bone marrow macrophages by IL-6. Augmented STAT3 activation was crucial for upregulating the expression of Mmp9 and Bv8 genes and downregulating the expression of Trail and Rab27a genes in neutrophils. Moreover, G-CSF/IL-6-modulated neutrophils could not efficiently release azurophilic granules because of downregulation of Rab27a and inefficient activation of PI3K and p38 MAPK pathways. Because of premodulation by G-CSF and IL-6, neutrophils in response to complex stimuli in tumor released much less myeloperoxidase, neutrophil elastase, and TRAIL, but showed much higher expression of Mmp9 and Bv8 genes. Taken together, these results demonstrate that G-CSF and IL-6, despite their well-known physiological functions, could modulate the activation potential of signaling pathways in neutrophils, resulting in the production or release of the above-mentioned factors in a way that favors tumor angiogenesis and tumor growth.
中性粒细胞具有抗肿瘤潜能。然而，近年来已充分证明中性粒细胞具有促进肿瘤生长的作用。迄今为止，尚不清楚是什么导致中性粒细胞功能从抑制肿瘤转变为促进肿瘤。在本文中，我们报告了鼠类中性粒细胞功能的这种转变发生在骨髓中，并且需要 IL-6 与 G-CSF 的合作来实现这种转变。IL-6 与 G-CSF 共同作用于骨髓中的中性粒细胞，改变了中性粒细胞中信号通路的激活潜能，特别是 STAT3。G-CSF 和 IL-6 的共刺激诱导中性粒细胞中磷酸化 STAT3 的水平升高，而 IL-6 通过下调骨髓巨噬细胞中的 IFN-β 表达而上调 STAT3 表达，进一步增加了 STAT3 的磷酸化水平。增强的 STAT3 激活对于上调 Mmp9 和 Bv8 基因的表达以及下调 Trail 和 Rab27a 基因的表达至关重要。此外，由于 Rab27a 的下调以及 PI3K 和 p38 MAPK 途径的激活效率降低，G-CSF/IL-6 调节的中性粒细胞不能有效地释放嗜中性粒细胞颗粒。由于 G-CSF 和 IL-6 的预先调节，中性粒细胞在响应肿瘤中的复杂刺激时释放的髓过氧化物酶、中性粒细胞弹性蛋白酶和 TRAIL 减少，但显示出更高的 Mmp9 和 Bv8 基因表达。总之，这些结果表明，尽管 G-CSF 和 IL-6 具有众所周知的生理功能，但它们可以调节中性粒细胞中信号通路的激活潜能，从而以有利于肿瘤血管生成和肿瘤生长的方式产生或释放上述因子。
