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Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype
Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, because it can induce apoptosis in various tumor cells but not in most normal cells. Although it is well known that TRAIL and its receptors are expressed in many types of normal cells, includ...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569310/ https://www.ncbi.nlm.nih.gov/pubmed/26224317 http://dx.doi.org/10.1091/mbc.E15-04-0209 |
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author | Gao, Jing Wang, Dongsheng Liu, Dan Liu, Min Ge, Yehua Jiang, Minghong Liu, Yanxin Zheng, Dexian |
author_facet | Gao, Jing Wang, Dongsheng Liu, Dan Liu, Min Ge, Yehua Jiang, Minghong Liu, Yanxin Zheng, Dexian |
author_sort | Gao, Jing |
collection | PubMed |
description | Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, because it can induce apoptosis in various tumor cells but not in most normal cells. Although it is well known that TRAIL and its receptors are expressed in many types of normal cells, including immune cells, their immunological effects and regulatory mechanisms are still obscure. In the present study, we demonstrated that TRAIL affected the activity of NF-κB (nuclear factor-κB) and the expression of its downstream proinflammatory cytokines IL-1β (interleukin-1β), IL-6, and tumor necrosis factor α in macrophages. TRAIL also induced microRNA-146a (miR-146a) expression in an NF-κB–dependent manner. As a result, miR-146a was involved as a negative-feedback regulator in the down-regulation of proinflammatory cytokine expression. In addition, the suppression of histone deacetylase (HDAC) activities by trichostatin A improved miR-146a expression due to the up-regulation of the DNA-binding activity of NF-κB at the miR-146a promoter in TRAIL-induced macrophages, suggesting that histone acetylation was involved in the suppression of miR-146a expression. Further investigation revealed that the HDAC subtype HDAC1 directly regulated the expression of miR-146a in TRAIL-stimulated macrophages. Finally, the TRAIL-sensitive human non small cell lung carcinoma cell line NCI-H460 was used to elucidate the physiological significance of TRAIL with respect to tumor-associated macrophages (TAMs). We demonstrated that TRAIL re-educated TAMs to an M1-like phenotype and induced cytotoxic effects in the tumor cells. These data provide new evidence for TRAIL in the immune regulation of macrophages and may shed light on TRAIL-based antitumor therapy in human patients. |
format | Online Article Text |
id | pubmed-4569310 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-45693102015-11-30 Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype Gao, Jing Wang, Dongsheng Liu, Dan Liu, Min Ge, Yehua Jiang, Minghong Liu, Yanxin Zheng, Dexian Mol Biol Cell Articles Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a promising candidate for cancer therapy, because it can induce apoptosis in various tumor cells but not in most normal cells. Although it is well known that TRAIL and its receptors are expressed in many types of normal cells, including immune cells, their immunological effects and regulatory mechanisms are still obscure. In the present study, we demonstrated that TRAIL affected the activity of NF-κB (nuclear factor-κB) and the expression of its downstream proinflammatory cytokines IL-1β (interleukin-1β), IL-6, and tumor necrosis factor α in macrophages. TRAIL also induced microRNA-146a (miR-146a) expression in an NF-κB–dependent manner. As a result, miR-146a was involved as a negative-feedback regulator in the down-regulation of proinflammatory cytokine expression. In addition, the suppression of histone deacetylase (HDAC) activities by trichostatin A improved miR-146a expression due to the up-regulation of the DNA-binding activity of NF-κB at the miR-146a promoter in TRAIL-induced macrophages, suggesting that histone acetylation was involved in the suppression of miR-146a expression. Further investigation revealed that the HDAC subtype HDAC1 directly regulated the expression of miR-146a in TRAIL-stimulated macrophages. Finally, the TRAIL-sensitive human non small cell lung carcinoma cell line NCI-H460 was used to elucidate the physiological significance of TRAIL with respect to tumor-associated macrophages (TAMs). We demonstrated that TRAIL re-educated TAMs to an M1-like phenotype and induced cytotoxic effects in the tumor cells. These data provide new evidence for TRAIL in the immune regulation of macrophages and may shed light on TRAIL-based antitumor therapy in human patients. The American Society for Cell Biology 2015-09-15 /pmc/articles/PMC4569310/ /pubmed/26224317 http://dx.doi.org/10.1091/mbc.E15-04-0209 Text en © 2015 Gao et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. |
spellingShingle | Articles Gao, Jing Wang, Dongsheng Liu, Dan Liu, Min Ge, Yehua Jiang, Minghong Liu, Yanxin Zheng, Dexian Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype |
title | Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype |
title_full | Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype |
title_fullStr | Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype |
title_full_unstemmed | Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype |
title_short | Tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype |
title_sort | tumor necrosis factor–related apoptosis-inducing ligand induces the expression of proinflammatory cytokines in macrophages and re-educates tumor-associated macrophages to an antitumor phenotype |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4569310/ https://www.ncbi.nlm.nih.gov/pubmed/26224317 http://dx.doi.org/10.1091/mbc.E15-04-0209 |
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