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Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice
BACKGROUND: Ruxolitinib is an inhibitor of Janus kinases (JAK) 1/2. It was authorised recently by the U.S. Food and Drug Administration (FDA) as a new Myelofibrosis treatment. In this study, we identified ruxolitinib as a new inhibitor of nitric oxide (NO) production in response to lipopolysaccharid...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AME Publishing Company
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214887/ https://www.ncbi.nlm.nih.gov/pubmed/32411769 http://dx.doi.org/10.21037/atm-20-2972 |
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author | Li, Li He, Xingfeng Wang, Xingtong Sun, Yu Wu, Guosheng Fang, He Wang, Chen Luo, Pengfei Xia, Zhaofan |
author_facet | Li, Li He, Xingfeng Wang, Xingtong Sun, Yu Wu, Guosheng Fang, He Wang, Chen Luo, Pengfei Xia, Zhaofan |
author_sort | Li, Li |
collection | PubMed |
description | BACKGROUND: Ruxolitinib is an inhibitor of Janus kinases (JAK) 1/2. It was authorised recently by the U.S. Food and Drug Administration (FDA) as a new Myelofibrosis treatment. In this study, we identified ruxolitinib as a new inhibitor of nitric oxide (NO) production in response to lipopolysaccharide (LPS)stimulation of RAW 264.7 cells. METHODS: In vitro direct effects of ruxolitinib were determined through NO production on RAW 264.7 cells. Also the expression level of iNOS, TNF-α and IL-6 were detected by Western Blotting and qRT-PCR. In vivo therapeutic effects of ruxolitinib on sepsis were evaluated by an endotoxemia model with C57 mice. The survival was calculated and histopathological damage of organs was observed by HE. Cytokines in serum were detected by Mouse Cytokine Array Panel. RESULTS: Ruxolitinib was found to significantly reduce NO production, inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 expression, suggesting that ruxolitinib blocks LPS signaling that leads to pro-inflammatory factor expression. Furthermore, the inhibitory effects of ruxolitinib contributed to the survival of septic mice by 70% and pro-inflammatory cytokines in serum declined apparently. The results taken together indicate that ruxolitinib can significantly suppress LPS-stimulated NO production and improve the survival of septic mice, perhaps by interfering with the NF-κB pathway. CONCLUSIONS: These findings suggest ruxolitinib might be a possible therapeutic candidate for sepsis therapy. |
format | Online Article Text |
id | pubmed-7214887 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | AME Publishing Company |
record_format | MEDLINE/PubMed |
spelling | pubmed-72148872020-05-14 Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice Li, Li He, Xingfeng Wang, Xingtong Sun, Yu Wu, Guosheng Fang, He Wang, Chen Luo, Pengfei Xia, Zhaofan Ann Transl Med Original Article BACKGROUND: Ruxolitinib is an inhibitor of Janus kinases (JAK) 1/2. It was authorised recently by the U.S. Food and Drug Administration (FDA) as a new Myelofibrosis treatment. In this study, we identified ruxolitinib as a new inhibitor of nitric oxide (NO) production in response to lipopolysaccharide (LPS)stimulation of RAW 264.7 cells. METHODS: In vitro direct effects of ruxolitinib were determined through NO production on RAW 264.7 cells. Also the expression level of iNOS, TNF-α and IL-6 were detected by Western Blotting and qRT-PCR. In vivo therapeutic effects of ruxolitinib on sepsis were evaluated by an endotoxemia model with C57 mice. The survival was calculated and histopathological damage of organs was observed by HE. Cytokines in serum were detected by Mouse Cytokine Array Panel. RESULTS: Ruxolitinib was found to significantly reduce NO production, inducible nitric oxide synthase (iNOS), TNF-α, and IL-6 expression, suggesting that ruxolitinib blocks LPS signaling that leads to pro-inflammatory factor expression. Furthermore, the inhibitory effects of ruxolitinib contributed to the survival of septic mice by 70% and pro-inflammatory cytokines in serum declined apparently. The results taken together indicate that ruxolitinib can significantly suppress LPS-stimulated NO production and improve the survival of septic mice, perhaps by interfering with the NF-κB pathway. CONCLUSIONS: These findings suggest ruxolitinib might be a possible therapeutic candidate for sepsis therapy. AME Publishing Company 2020-04 /pmc/articles/PMC7214887/ /pubmed/32411769 http://dx.doi.org/10.21037/atm-20-2972 Text en 2020 Annals of Translational Medicine. All rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0 (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Original Article Li, Li He, Xingfeng Wang, Xingtong Sun, Yu Wu, Guosheng Fang, He Wang, Chen Luo, Pengfei Xia, Zhaofan Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice |
title | Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice |
title_full | Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice |
title_fullStr | Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice |
title_full_unstemmed | Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice |
title_short | Ruxolitinib protects lipopolysaccharide (LPS)-induced sepsis through inhibition of nitric oxide production in mice |
title_sort | ruxolitinib protects lipopolysaccharide (lps)-induced sepsis through inhibition of nitric oxide production in mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214887/ https://www.ncbi.nlm.nih.gov/pubmed/32411769 http://dx.doi.org/10.21037/atm-20-2972 |
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