TGF-β1 activates neutrophil signaling and gene expression but not migration.
TGF-β1 activates neutrophil signaling and gene expression but not migration.
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DOI：
10.1371/journal.pone.0290886
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发表时间：
2023
期刊：
影响因子：
3.7
通讯作者：
Parent, Carole A.
中科院分区：
文献类型：
--
作者：
Hein, Lauren E.;SenGupta, Shuvasree;Gunasekaran, Gaurie;Johnson, Craig N.;Parent, Carole A.
肿瘤相关中性粒细胞存在于许多类型的癌症中，并且经常被报告为导致负面结果。据报道，肿瘤微环境中转化生长因子-β（TGF-β）的存在有助于嗜中性粒细胞向更促肿瘤表型倾斜。然而，TGF-β对中性粒细胞信号传导和迁移的影响尚不清楚。我们试图表征原代人中性粒细胞和嗜中性粒细胞样细胞系HL-60中的TGF-β信号传导，并确定其是否直接诱导中性粒细胞迁移。我们发现TGF-β1在transwell或琼脂糖迁移试验中不诱导中性粒细胞趋化。TGF-β1确实以时间和剂量依赖性方式激活中性粒细胞中通过SMAD 3的经典信号传导和通过ERK 1/2的非经典信号传导。此外，浸润性乳腺癌细胞的肿瘤条件培养基（TCM）中存在的TGF-β1导致SMAD 3活化。我们发现，中药诱导中性粒细胞分泌白三烯B4（LTB 4），这是一种重要的脂质介质，扩大范围的中性粒细胞招聘。然而，单独的TGF-β1不诱导LTB 4的分泌。RNA测序显示TGF-β1和TCM改变HL-60细胞中的基因表达，包括促肿瘤抑瘤素M（OSM）和血管内皮生长因子A（VEGFA）的mRNA水平。这些关于TGF-β1对中性粒细胞信号传导、迁移和基因表达的作用和影响的新见解对理解肿瘤微环境中发生的中性粒细胞变化具有重要意义。
Tumor-associated neutrophils are found in many types of cancer and are often reported to contribute to negative outcomes. The presence of transforming growth factor-beta (TGF-β) in the tumor microenvironment reportedly contributes to the skewing of neutrophils to a more pro-tumor phenotype. The effects of TGF-β on neutrophil signaling and migration are, however, unclear. We sought to characterize TGF-β signaling in both primary human neutrophils and the neutrophil-like cell line HL-60 and determine whether it directly induces neutrophil migration. We found that TGF-β1 does not induce neutrophil chemotaxis in transwell or underagarose migration assays. TGF-β1 does activate canonical signaling through SMAD3 and noncanonical signaling through ERK1/2 in neutrophils in a time- and dose-dependent manner. Additionally, TGF-β1 present in the tumor-conditioned media (TCM) of invasive breast cancer cells results in SMAD3 activation. We discovered that TCM induces neutrophils to secrete leukotriene B4 (LTB4), which is a lipid mediator important for amplifying the range of neutrophil recruitment. However, TGF-β1 alone does not induce secretion of LTB4. RNA-sequencing revealed that TGF-β1 and TCM alter gene expression in HL-60 cells, including the mRNA levels of the pro-tumor oncostatin M (OSM) and vascular endothelial growth factor A (VEGFA). These new insights into the role and impact of TGF-β1 on neutrophil signaling, migration, and gene expression have significant implications in the understanding of the changes in neutrophils that occur in the tumor microenvironment.
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影响因子：
4.4
作者：
Jeon KI;Kumar A;Wozniak KT;Nehrke K;Huxlin KR
通讯作者：
Huxlin KR
影响因子：
14.9
作者：
Gillespie M;Jassal B;Stephan R;Milacic M;Rothfels K;Senff-Ribeiro A;Griss J;Sevilla C;Matthews L;Gong C;Deng C;Varusai T;Ragueneau E;Haider Y;May B;Shamovsky V;Weiser J;Brunson T;Sanati N;Beckman L;Shao X;Fabregat A;Sidiropoulos K;Murillo J;Viteri G;Cook J;Shorser S;Bader G;Demir E;Sander C;Haw R;Wu G;Stein L;Hermjakob H;D'Eustachio P
通讯作者：
D'Eustachio P
影响因子：
50.3
作者：
Granot Z;Henke E;Comen EA;King TA;Norton L;Benezra R
通讯作者：
Benezra R
影响因子：
4.8
作者：
Fang, Wei Bin;Jokar, Iman;Cheng, Nikki
通讯作者：
Cheng, Nikki
影响因子：
50.3
作者：
Jackstadt, Rene;van Hooff, Sander R.;Sansom, Owen J.
通讯作者：
Sansom, Owen J.