Targeting the 15-keto-PGE2-PTGR2 axis modulates systemic inflammation and survival in experimental sepsis

Chen, Ing‐Jung; Hee, Siow‐Wey; Liao, Chun-Hsing; Lin, Shuei Liong; Su, Lynn; Shun, Chia‐Tung; Chuang, Lee‐Ming

doi:10.1016/j.freeradbiomed.2017.11.016

Cited by 32 publications

(33 citation statements)

References 73 publications

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“…15-PGDH catalyze the conversion of 15-hydroxy group of PGE 2 into 15-keto-PGE2 (15k-PGE2), which further catalyzed by prostaglandin reductase 2 (PTGR2). Exogenous 15k-PGE2 treatment or PTGR2 knockdown yielded the antioxidative transcription factor increase in LPS-stimulated RAW264.7 cells (Chen et al, 2018). Therefore, we speculate that 15-PGDH may regulate oxidative stress via COX-2/PGE2/EP4 signaling axis.…”

Section: Discussionmentioning

confidence: 74%

Pharmacologic Blockade of 15-PGDH Protects Against Acute Renal Injury Induced by LPS in Mice

Miao

Liu

et al. 2020

Front. Physiol.

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Prostaglandin pathway plays multiple roles in various physiological and pathological conditions. The present study aimed to investigate the effect of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a key enzyme in the degradation of prostaglandins, on lipopolysaccharide (LPS)-induced acute kidney injury (AKI) in mice. In this study, male C57BL/6J mice were injected intraperitoneally with LPS (10 mg/kg). SW033291, a potent small-molecule inhibitor of 15-PGDH, was used to investigate the therapeutic potential of 15-PGDH inhibition on LPS-induced AKI. We discovered that the expression of 15-PGDH protein was upregulated in kidneys of LPS-stimulated mice, and it was mainly localized in the cytoplasm of renal tubular epithelial cells in renal cortex and outer medulla. SW033291 administration improved the survival rates of mice and attenuated renal injury of mice that were challenged by LPS. Additionally, inhibition of 15-PGDH also reversed LPS-induced apoptosis of renal cells, increased expression of anti-apoptotic protein Bcl-2, and downregulated expression of Fas, caspase-3, and caspase-8. Pretreatment of SW033291 enhanced autophagy in kidney cells after LPS stimulation. Our data also showed that inhibition of 15-PGDH relieved the level of lipid peroxidation and downregulated NADPH oxidase subunits induced by LPS in mice kidneys but had no significant effect on the release of inflammatory factors, such as IL-6, IL-1β, TNF-α, and MCP-1. Our study demonstrated that inhibition of 15-PGDH could alleviate LPS-induced AKI by regulating the apoptosis, autophagy, and oxidative stress rather than inflammation in mice.

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Section: Discussionmentioning

confidence: 74%

Pharmacologic Blockade of 15-PGDH Protects Against Acute Renal Injury Induced by LPS in Mice

Miao

Liu

et al. 2020

Front. Physiol.

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“…Furthermore, addition of PGE2 alone was sufficient to increase the DA Hif-1α-induced tnfa:GFP expression (Figures 4A,B). These tnfa:GFP activating effects were not observed by addition of exogenous 15-keto prostaglandin E2, an immunologically inactive degradation product of PGE2 (Figures 5C,D) (35, 42, 43). These data indicate that Hif-1α-induced tnfa:GFP requires active prostaglandin E2.…”

Section: Resultsmentioning

confidence: 85%

Hypoxia Induces Macrophage tnfa Expression via Cyclooxygenase and Prostaglandin E2 in vivo

Lewis

Elks

2019

Front. Immunol.

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Macrophage phenotypes are poorly characterized in disease systems in vivo. Appropriate macrophage activation requires complex coordination of local microenvironmental cues and cytokine signaling. If the molecular mechanisms underpinning macrophage activation were better understood, macrophages could be pharmacologically tuned during disease situations. Here, using zebrafish tnfa:GFP transgenic lines as in vivo readouts, we show that physiological hypoxia and stabilization of Hif-1α promotes macrophage tnfa expression. We demonstrate a new mechanism of Hif-1α-induced macrophage tnfa expression via a cyclooxygenase/prostaglandin E2 axis. These findings uncover a macrophage HIF/COX/TNF axis that links microenvironmental cues to macrophage phenotype, with important implications during inflammation, infection, and cancer, where hypoxia is a common microenvironmental feature and where cyclooxygenase and TNF are major mechanistic players.

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“…PPARγ also regulates intracellular lipolysis in adipose tissue [75], and activated adipose PPARγ could explain the elevated free fatty acids in sPTB subjects. On the other hand, 15-Keto PGE2 was positively associated with better LPS-induced sepsis survival and the suppression of proinflammatory cytokines production in murine macrophages [76]. Since sPTB was associated with elevated levels of circulating pro-inflammatory cytokines, the increased 15-Keto PGE2 is consistent with a modulating anti-inflammatory response at mid-gestation.…”

Section: Plos Onementioning

confidence: 87%

Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index

et al. 2020

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Spontaneous preterm birth (sPTB) is a major cause of infant morbidity and mortality. While metabolic changes leading to preterm birth are unknown, several factors including dyslipidemia and inflammation have been implicated and paradoxically both low (<18.5 kg/m2) and high (>30 kg/m2) body mass indices (BMIs) are risk factors for this condition. The objective of the study was to identify BMI-associated metabolic perturbations and potential mid-gestation serum biomarkers of preterm birth in a cohort of underweight, normal weight and obese women experiencing either sPTB or full-term deliveries (n = 102; n = 17/group). For this purpose, we combined untargeted metabolomics and lipidomics with targeted metabolic profiling of major regulators of inflammation and metabolism, including oxylipins, endocannabinoids, bile acids and ceramides. Women who were obese and had sPTB showed elevated oxidative stress and dyslipidemia characterized by elevated serum free fatty acids. Women who were underweight-associated sPTB also showed evidence of dyslipidemia characterized by elevated phospholipids, unsaturated triglycerides, sphingomyelins, cholesteryl esters and long-chain acylcarnitines. In normal weight women experiencing sPTB, the relative abundance of 14(15)-epoxyeicosatrienoic acid and 14,15-dihydroxyeicosatrienoic acids to other regioisomers were altered at mid-pregnancy. This phenomenon is not yet associated with any biological process, but may be linked to estrogen metabolism. These changes were differentially modulated across BMI groups. In conclusion, using metabolomics we observed distinct BMI-dependent metabolic manifestations among women who had sPTB. These observations suggest the potential to predict sPTB mid-gestation using a new set of metabolomic markers and BMI stratification. This study opens the door to further investigate the role of cytochrome P450/epoxide hydrolase metabolism in sPTB.

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Targeting the 15-keto-PGE2-PTGR2 axis modulates systemic inflammation and survival in experimental sepsis

Cited by 32 publications

References 73 publications

Pharmacologic Blockade of 15-PGDH Protects Against Acute Renal Injury Induced by LPS in Mice

Pharmacologic Blockade of 15-PGDH Protects Against Acute Renal Injury Induced by LPS in Mice

Hypoxia Induces Macrophage tnfa Expression via Cyclooxygenase and Prostaglandin E2 in vivo

Mid-gestation serum lipidomic profile associations with spontaneous preterm birth are influenced by body mass index

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