FTY720P Upregulates the Na+/K+ ATPase in HepG2 Cells by Activating S1PR3 and Inducing PGE2 Release

Chakkour, Mohamed; Kreydiyyeh, Sawsan Ibrahim

doi:10.33594/000000155

Cited by 9 publications

(7 citation statements)

References 46 publications

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“…Several reports have documented that PI3K, which is one of the wortmannin targets, regulates crosstalk between V-ATPase and F-actin in osteoclasts ( 55 ) or that PI3K has been involved in “regulated V-ATPase assembly” in dendritic cells ( 56 ). It has been shown in some studies that the S1PR2/S1PR3 axis regulated Na + /K + ATPase in the hepatocellular carcinoma cell line ( 57 , 58 ), while others have indicated that Na + /K + ATPase might serve as an alternative for V-ATPase in astrocytes ( 59 ). Considering V-ATPase inhibitor (Baf A1) enhanced NET formation in parallel with depletion of lysosomal proteins ( Figure 8 ) while S1PR2 ligation restored these proteins, we assumed S1PR2/3 signaling is involved in the reciprocal regulation of V-ATPase.…”

Section: Discussionmentioning

confidence: 99%

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation

Hirao

Kojima

Dery

et al. 2023

Journal of Clinical Investigation

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Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen–related cell adhesion molecule 1 (CEACAM1, CC1 , or CD66a ) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P–S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.

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Section: Discussionmentioning

confidence: 99%

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation

Hirao

Kojima

Dery

et al. 2023

Journal of Clinical Investigation

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“…However, the pharmacodynamic reduction in heart rate can be circumvented by implementation of drug titration for the first 4-5 days of treatment, as demonstrated in most patients being treated with siponimod [5] and in the ozanimod trials [11,12]. Fingolimod has also been shown to induce the inflammatory mediator cyclooxygenase 2 (COX2) in rat astrocyte cell cultures [41], and increase COX2 expression in mice and human HepG2 cell cultures via S1PR 3 [42,43], suggesting that activity at this receptor may contribute to inflammatory processes. However, unlike S1P, in vitro studies have shown that fingolimod may be a partial agonist of S1PR 3 compared with S1P, and possibly have antagonistic properties under certain conditions [44][45][46], so the biological significance of this observation is unclear.…”

Section: Figmentioning

confidence: 99%

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

Chun

Giovannoni

Hunter

2020

Drugs

107

146

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Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR 1 to S1PR 5 . Previous and continuing investigation of the S1P pathway has led to the approval of three S1PR modulators, fingolimod, siponimod and ozanimod, as medicines for patients with multiple sclerosis (MS), as well as the identification of new S1PR modulators currently in clinical development, including ponesimod and etrasimod. S1PR modulators have complex effects on S1PRs, in some cases acting both as traditional agonists as well as agonists that produce functional antagonism. S1PR subtype specificity influences their downstream effects, including aspects of their benefit:risk profile. Some S1PR modulators are prodrugs, which require metabolic modification such as phosphorylation via sphingosine kinases, resulting in different pharmacokinetics and bioavailability, contrasting with others that are direct modulators of the receptors. The complex interplay of these characteristics dictates the clinical profile of S1PR modulators. This review focuses on the S1P pathway, the characteristics and S1PR binding profiles of S1PR modulators, the mechanisms of action of S1PR modulators with regard to immune cell trafficking and neuroprotection in MS, together with a summary of the clinical effectiveness of the S1PR modulators that are approved or in late-stage development for patients with MS. Electronic supplementary material The online version of this article (10.1007/s40265-020-01431-8) contains supplementary material, which is available to authorized users.

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“…We identified PGE 2 as a regenerative factor both in 2D and 3D human tissue cultures and as a mediator of the IL1β-induced response. Previous work implicating PGE 2 in this pathway has not investigated its effect on primary human hepatocytes ( 55 – 57 ). In the future, treatment with PGE 2 might be considered for use as a preconditioning agent for liver transplants, or PGE 2 -releasing depots could be incorporated into engineered grafts in order to promote the expansion of engrafted hepatocytes in vivo, even in the absence of an injury stimulus.…”

Section: Discussionmentioning

confidence: 99%

A vascularized model of the human liver mimics regenerative responses

Chhabra

Song

Grzelak

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Liver regeneration is a well-orchestrated process that is typically studied in animal models. Although previous animal studies have offered many insights into liver regeneration, human biology is less well understood. To this end, we developed a three-dimensional (3D) platform called structurally vascularized hepatic ensembles for analyzing regeneration (SHEAR) to model multiple aspects of human liver regeneration. SHEAR enables control over hemodynamic alterations to mimic those that occur during liver injury and regeneration and supports the administration of biochemical inputs such as cytokines and paracrine interactions with endothelial cells. We found that exposing the endothelium-lined channel to fluid flow led to increased secretion of regeneration-associated factors. Stimulation with relevant cytokines not only amplified the secretory response, but also induced cell-cycle entry of primary human hepatocytes (PHHs) embedded within the device. Further, we identified endothelial-derived mediators that are sufficient to initiate proliferation of PHHs in this context. Collectively, the data presented here underscore the importance of multicellular models that can recapitulate high-level tissue functions and demonstrate that the SHEAR device can be used to discover and validate conditions that promote human liver regeneration.

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FTY720P Upregulates the Na+/K+ ATPase in HepG2 Cells by Activating S1PR3 and Inducing PGE2 Release

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 9 publications

References 46 publications

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation

Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation

Sphingosine 1-phosphate Receptor Modulator Therapy for Multiple Sclerosis: Differential Downstream Receptor Signalling and Clinical Profile Effects

A vascularized model of the human liver mimics regenerative responses

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