Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation
Abstract Background Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-07-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-020-00603-z |
| _version_ | 1818478275341582336 |
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| author | Shunyao Xu Xiaojun Pan Lingjie Mao Hao Pan Wenwei Xu Yufeng Hu Xueshu Yu Zhiqiang Chen Songzan Qian Yincai Ye Yueyue Huang Jingye Pan |
| author_facet | Shunyao Xu Xiaojun Pan Lingjie Mao Hao Pan Wenwei Xu Yufeng Hu Xueshu Yu Zhiqiang Chen Songzan Qian Yincai Ye Yueyue Huang Jingye Pan |
| author_sort | Shunyao Xu |
| collection | DOAJ |
| description | Abstract Background Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis. Methods Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling. Results Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition. Conclusions Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis. Video Abstract |
| first_indexed | 2024-12-10T09:45:52Z |
| format | Article |
| id | doaj.art-26bc6ffbd9ac4e74a443e7b5c343ec39 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-10T09:45:52Z |
| publishDate | 2020-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-26bc6ffbd9ac4e74a443e7b5c343ec392022-12-22T01:53:50ZengBMCCell Communication and Signaling1478-811X2020-07-0118111310.1186/s12964-020-00603-zPhospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulationShunyao Xu0Xiaojun Pan1Lingjie Mao2Hao Pan3Wenwei Xu4Yufeng Hu5Xueshu Yu6Zhiqiang Chen7Songzan Qian8Yincai Ye9Yueyue Huang10Jingye Pan11Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityWenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Blood Transfusion, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical UniversityAbstract Background Sepsis is an infection-induced aggressive and life-threatening organ dysfunction with high morbidity and mortality worldwide. Infection-associated inflammation and coagulation promote the progression of adverse outcomes in sepsis. Here, we report that phospho-Tyr705 of STAT3 (pY-STAT3), not total STAT3, contributes to systemic inflammation and coagulopathy in sepsis. Methods Cecal ligation and puncture (CLP)-induced septic mice were treated with BP-1-102, Napabucasin, or vehicle control respectively and then assessed for systemic inflammation, coagulation response, lung function and survival. Human pulmonary microvascular endothelial cells (HPMECs) and Raw264.7 cells were exposed to lipopolysaccharide (LPS) with pharmacological or genetic inhibition of pY-STAT3. Cells were assessed for inflammatory and coagulant factor expression, cell function and signaling. Results Pharmacological inhibition of pY-STAT3 expression by BP-1-102 reduced the proinflammatory factors, suppressed coagulation activation, attenuated lung injury, alleviated vascular leakage and improved the survival rate in septic mice. Pharmacological or genetic inhibition of pY-STAT3 diminished LPS-induced cytokine production in macrophages and protected pulmonary endothelial cells via the IL-6/JAK2/STAT3, NF-κB and MAPK signaling pathways. Moreover, the increase in procoagulant indicators induced by sepsis such as tissue factor (TF), the thrombin-antithrombin complex (TAT) and D-Dimer were down-regulated by pY-STAT3 inhibition. Conclusions Our results revealed a therapeutic role of pY-STAT3 in modulating the inflammatory response and defective coagulation during sepsis. Video Abstracthttp://link.springer.com/article/10.1186/s12964-020-00603-zSepsisSTAT3InflammationCoagulation |
| spellingShingle | Shunyao Xu Xiaojun Pan Lingjie Mao Hao Pan Wenwei Xu Yufeng Hu Xueshu Yu Zhiqiang Chen Songzan Qian Yincai Ye Yueyue Huang Jingye Pan Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation Cell Communication and Signaling Sepsis STAT3 Inflammation Coagulation |
| title | Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation |
| title_full | Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation |
| title_fullStr | Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation |
| title_full_unstemmed | Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation |
| title_short | Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation |
| title_sort | phospho tyr705 of stat3 is a therapeutic target for sepsis through regulating inflammation and coagulation |
| topic | Sepsis STAT3 Inflammation Coagulation |
| url | http://link.springer.com/article/10.1186/s12964-020-00603-z |
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