Chen, Ing-JungIng-JungChenHee, Siow-WeySiow-WeyHeeLiao, Chun-HsingChun-HsingLiaoLin, Shih-YaoShih-YaoLinSu, LynnLynnSuCHIA-TUNG SHUNLEE-MING CHUANG2023-02-082023-02-082018-02-010891-5849https://scholars.lib.ntu.edu.tw/handle/123456789/627759Sepsis 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.en15-keto-PGE2; Inflammation; Keap1; Macrophages; Nrf2; PTGR2; Sepsisjournal article10.1016/j.freeradbiomed.2017.11.016291754862-s2.0-85036583073WOS:000419709200011https://api.elsevier.com/content/abstract/scopus_id/85036583073