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Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species
Prostaglandin D(2) (PGD(2)) is a potent lipid mediator that controls inflammation, and its dysregulation has been implicated in diverse inflammatory disorders. Despite significant progress made in understanding the role of PGD(2) as a key regulator of immune responses, the molecular mechanism underl...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723016/ https://www.ncbi.nlm.nih.gov/pubmed/29255467 http://dx.doi.org/10.3389/fimmu.2017.01720 |
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author | Kim, Ji-Yun Choi, Go-Eun Yoo, Hyun Ju Kim, Hun Sik |
author_facet | Kim, Ji-Yun Choi, Go-Eun Yoo, Hyun Ju Kim, Hun Sik |
author_sort | Kim, Ji-Yun |
collection | PubMed |
description | Prostaglandin D(2) (PGD(2)) is a potent lipid mediator that controls inflammation, and its dysregulation has been implicated in diverse inflammatory disorders. Despite significant progress made in understanding the role of PGD(2) as a key regulator of immune responses, the molecular mechanism underlying PGD(2) production remains unclear, particularly upon challenge with different and multiple inflammatory stimuli. Interferons (IFNs) potentiate macrophage activation and act in concert with exogenous inflammatory mediators such as toll-like receptor (TLR) ligands to amplify inflammatory responses. A recent study found that IFN-γ enhanced lipopolysaccharide-induced PGD(2) production, indicating a role of IFNs in PGD(2) regulation. Here, we demonstrate that TLR-induced PGD(2) production by macrophages was significantly potentiated by signaling common to IFN-β and IFN-γ in a signal transducer and activators of transcription (STAT)1-dependent mechanism. Such potentiation by IFNs was also observed for PGE(2) production, despite the differential regulation of PGD synthase and PGE synthase isoforms mediating PGD(2) and PGE(2) production under inflammatory conditions. Mechanistic analysis revealed that the generation of intracellular reactive oxygen species (ROS) was remarkably potentiated by IFNs and required for PGD(2) production, but was nullified by STAT1 deficiency. Conversely, the regulation of STAT1 level and activity by IFNs was largely dependent on ROS levels. Using a model of zymosan-induced peritonitis, the relevance of this finding in vivo was supported by marked inhibition of PGD(2) and ROS produced in peritoneal exudate cells by STAT1 deficiency. Collectively, our findings suggest that IFNs, although not activating on their own, are potent amplifiers of TLR-induced PGD(2) production via positive-feedback regulation between STAT1 and ROS. |
format | Online Article Text |
id | pubmed-5723016 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-57230162017-12-18 Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species Kim, Ji-Yun Choi, Go-Eun Yoo, Hyun Ju Kim, Hun Sik Front Immunol Immunology Prostaglandin D(2) (PGD(2)) is a potent lipid mediator that controls inflammation, and its dysregulation has been implicated in diverse inflammatory disorders. Despite significant progress made in understanding the role of PGD(2) as a key regulator of immune responses, the molecular mechanism underlying PGD(2) production remains unclear, particularly upon challenge with different and multiple inflammatory stimuli. Interferons (IFNs) potentiate macrophage activation and act in concert with exogenous inflammatory mediators such as toll-like receptor (TLR) ligands to amplify inflammatory responses. A recent study found that IFN-γ enhanced lipopolysaccharide-induced PGD(2) production, indicating a role of IFNs in PGD(2) regulation. Here, we demonstrate that TLR-induced PGD(2) production by macrophages was significantly potentiated by signaling common to IFN-β and IFN-γ in a signal transducer and activators of transcription (STAT)1-dependent mechanism. Such potentiation by IFNs was also observed for PGE(2) production, despite the differential regulation of PGD synthase and PGE synthase isoforms mediating PGD(2) and PGE(2) production under inflammatory conditions. Mechanistic analysis revealed that the generation of intracellular reactive oxygen species (ROS) was remarkably potentiated by IFNs and required for PGD(2) production, but was nullified by STAT1 deficiency. Conversely, the regulation of STAT1 level and activity by IFNs was largely dependent on ROS levels. Using a model of zymosan-induced peritonitis, the relevance of this finding in vivo was supported by marked inhibition of PGD(2) and ROS produced in peritoneal exudate cells by STAT1 deficiency. Collectively, our findings suggest that IFNs, although not activating on their own, are potent amplifiers of TLR-induced PGD(2) production via positive-feedback regulation between STAT1 and ROS. Frontiers Media S.A. 2017-12-04 /pmc/articles/PMC5723016/ /pubmed/29255467 http://dx.doi.org/10.3389/fimmu.2017.01720 Text en Copyright © 2017 Kim, Choi, Yoo and Kim. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Kim, Ji-Yun Choi, Go-Eun Yoo, Hyun Ju Kim, Hun Sik Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species |
title | Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species |
title_full | Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species |
title_fullStr | Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species |
title_full_unstemmed | Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species |
title_short | Interferon Potentiates Toll-Like Receptor-Induced Prostaglandin D(2) Production through Positive Feedback Regulation between Signal Transducer and Activators of Transcription 1 and Reactive Oxygen Species |
title_sort | interferon potentiates toll-like receptor-induced prostaglandin d(2) production through positive feedback regulation between signal transducer and activators of transcription 1 and reactive oxygen species |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723016/ https://www.ncbi.nlm.nih.gov/pubmed/29255467 http://dx.doi.org/10.3389/fimmu.2017.01720 |
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