Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage
Background: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: Th...
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doaj-1030f46fbd8f4fc6978d288a88aa64502020-11-25T01:35:43ZengCell Physiol Biochem Press GmbH & Co KGCellular Physiology and Biochemistry1015-89871421-97782017-12-014462201221110.1159/000486025486025Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in MacrophageChengjun ZhuHua ShenLingjun ZhuFeng ZhaoYongqian ShuBackground: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. Results: PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β. Conclusion: PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression.https://www.karger.com/Article/FullText/486025HegdhrNSCLCTGF-βPAI-1TAMs |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Chengjun Zhu Hua Shen Lingjun Zhu Feng Zhao Yongqian Shu |
spellingShingle |
Chengjun Zhu Hua Shen Lingjun Zhu Feng Zhao Yongqian Shu Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage Cellular Physiology and Biochemistry Hegdhr NSCLC TGF-β PAI-1 TAMs |
author_facet |
Chengjun Zhu Hua Shen Lingjun Zhu Feng Zhao Yongqian Shu |
author_sort |
Chengjun Zhu |
title |
Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage |
title_short |
Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage |
title_full |
Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage |
title_fullStr |
Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage |
title_full_unstemmed |
Plasminogen Activator Inhibitor 1 Promotes Immunosuppression in Human Non-Small Cell Lung Cancers by Enhancing TGF-Β1 Expression in Macrophage |
title_sort |
plasminogen activator inhibitor 1 promotes immunosuppression in human non-small cell lung cancers by enhancing tgf-β1 expression in macrophage |
publisher |
Cell Physiol Biochem Press GmbH & Co KG |
series |
Cellular Physiology and Biochemistry |
issn |
1015-8987 1421-9778 |
publishDate |
2017-12-01 |
description |
Background: Plasminogen activator inhibitor-1 (PAI-1) has been regarded as a risk factor for thrombosis and atherosclerosis. Since it has been shown that PAI-1 can activate macrophages through Toll-like receptor-4, we sought to investigate the role of PAI-1 in the tumor microenvironment. Methods: The expression and distribution patterns of PAI-1 and transforming growth factor beta (TGF-β) were measured in 60 non-small cell lung cancer (NSCLC) tumors. A statistical correlation analysis was performed between PAI-1 and TGF-β expression and distribution in each tumor. The distribution of tumor-associated macrophages (TAMs) was also measured and its correlation to PAI-1 levels was analyzed. Levels of secreted CCL-17, CCL-22, IL-6 and TGF-β were measured in cell cultures of human macrophage cell lines THP-1 and U937 treated with PAI-1. Levels of secreted PAI-1 were monitored in cell cultures of human NSCLCs cell lines 95D and A549 treated with TGF-β. Secreted proteins were measured in cell culture supernatants using ELISA. Changes in downstream signaling pathways were investigated using western blot. Results: PAI-1 and TGF-β were found to be overexpressed in human NSCLCs. PAI-1 expression was tightly correlated to TGF-β expression as well as the percentage of TAMs. PAI-1 treatment increased the expression of TAM-associated cytokines and chemokines, including CCL-17, CCL-22, and IL-6. PAI-1 treatment was also observed to enhance TGF-β expression in macrophage cell lines through an IL-6 autocrine/paracrine manner. The effects on TGF-β expression were blocked by NF-κB and STAT3 inhibition. Interestingly, TGF-β also increased levels of secreted PAI-1 in NSCLC cells through SMAD3-dependent signaling, therefore resulting in a feed-forward loop. However, this loop could be blocked by NF-κB, STAT3 and SMAD3 signaling inhibition, as well as treatment with a high concentration of TGF-β. Conclusion: PAI-1 and TGF-β promote NSCLC tumor cells and TAMs and might be valuable targets for cancer immunosuppression. |
topic |
Hegdhr NSCLC TGF-β PAI-1 TAMs |
url |
https://www.karger.com/Article/FullText/486025 |
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