https://scholars.lib.ntu.edu.tw/handle/123456789/627759
標題: | Targeting the 15-keto-PGE2-PTGR2 axis modulates systemic inflammation and survival in experimental sepsis | 作者: | Chen, Ing-Jung Hee, Siow-Wey Liao, Chun-Hsing Lin, Shih-Yao Su, Lynn CHIA-TUNG SHUN LEE-MING CHUANG |
關鍵字: | 15-keto-PGE2; Inflammation; Keap1; Macrophages; Nrf2; PTGR2; Sepsis | 公開日期: | 1-二月-2018 | 出版社: | ELSEVIER SCIENCE INC | 卷: | 115 | 起(迄)頁: | 113 | 來源出版物: | Free radical biology & medicine | 摘要: | Sepsis is a systemic inflammation accompanied by multi-organ dysfunction due to microbial infection. Prostaglandins and their metabolites have long been studied for their importance in regulating the innate immune response. 15-keto-PGE2 (15k-PGE2) is a prostaglandin E2 (PGE2) metabolite, whose further processing is catalyzed by prostaglandin reductase 2 (PTGR2). We showed disruption of the Ptgr2 gene in mice improves the survival rate under both LPS- and cecum ligation/puncture (CLP)-induced experimental sepsis. Knockdown of PTGR2 showed significant accumulation of intracellular 15k-PGE2 in activated macrophages. Both PTGR2 knockdown and exogenous treatment with 15k-PGE2 resulted in reduced pro-inflammatory cytokines production in LPS-stimulated RAW264.7 cells or bone marrow-derived macrophages (BMDM). The same treatment in RAW264.7 and BMDM also led to increased levels of the anti-oxidative transcription factor, Nuclear factor (erythroid-2) related factor-2 (NRF2), augmented anti-oxidant response element (ARE)-mediated reporter activity and upregulated expression of the corresponding anti-oxidant genes. 15k-PGE2 further demonstrated modification to Kelch-like ECH-associated protein 1 (Keap1), a negative regulator of Nrf2, at cysteine 288 (Cys288) site post-translationally. Finally, 15k-PGE2-treated mice were found to be more resistant to experimental sepsis. Taken together, our study affirms the significance of PTGR2 and 15k-PGE2 in mitigating inflammatory responses and suggests a novel anti-oxidative and anti-inflammatory therapy for sepsis through targeting PTGR2 and administering15k-PGE2. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/627759 | ISSN: | 0891-5849 | DOI: | 10.1016/j.freeradbiomed.2017.11.016 |
顯示於: | 醫學系 |
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