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Veterinary immunology and immunopathology2017; 192; 33-40; doi: 10.1016/j.vetimm.2017.09.008

Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE2 in an in vitro equine inflammation model.

Abstract: Inhibition of prostaglandin E2 (PGE2) production effectively limits inflammation in horses, however nonspecific prostaglandin blockade via cyclooxygenase (COX) inhibition elicits deleterious gastrointestinal side effects in equine patients. Thus, more selective PGE2 targeting therapeutics are needed to treat inflammatory disease in horses. One potential target is microsomal prostaglandin E-synthase-1 (mPGES-1), which is the terminal enzyme downstream of COX-2 in the inducible PGE2 synthesis cascade. This enzyme has yet to be studied in equine leukocytes, which play a pivotal role in equine inflammatory disease. The objective of this study was to determine if mPGES-1 is a PGE2-selective anti-inflammatory target in equine leukocytes. To evaluate this objective, leukocyte-rich plasma (LRP) was isolated from equine whole blood collected via jugular venipuncture of six healthy adult horses of mixed breeds and genders. LRP was primed with granulocyte-monocyte colony-stimulating factor (GM-CSF) and stimulated with lipopolysaccharide (LPS) in the presence or absence of an mPGES-1 inhibitor (MF63), a COX-2 inhibitor (NS-398), or a nonselective COX inhibitor (indomethacin). Following treatment, mPGES-1 and COX-2 mRNA and protein levels were measured via qPCR and western blot, respectively, and PGE2, thromboxane (TXA2) and prostacyclin (PGI2) levels were measured in cellular supernatants via ELISA. This study revealed that LPS significantly increased mPGES-1 mRNA, but not protein levels in equine LRP as measured by qPCR and western blot, respectively. In contrast, COX-2 mRNA and protein were coordinately induced by LPS. Importantly, treatment of LPS-stimulated leukocytes with indomethacin and NS-398 significantly reduced extracellular concentrations of multiple prostanoids (PGE2, TXA2 and PGI2), while the mPGES-1 inhibitor MF63 selectively inhibited PGE2 production only. mPGES-1 inhibition also preserved higher basal levels of PGE2 production when compared to either COX inhibitor, which might be beneficial in a clinical setting. In conclusion, this work identifies mPGES-1 as a key regulator of PGE2 production and a PGE2-selective target in equine leukocytes. This study demonstrates that mPGES-1 is a potentially safer and effective therapeutic target for treatment of equine inflammatory disease when compared to traditional non-steroidal anti-inflammatory drugs.
Copyright © 2017 Elsevier B.V. All rights reserved.
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Publication Date: 2017-10-03 PubMed ID: 29042013PubMed Central: PMC6038704DOI: 10.1016/j.vetimm.2017.09.008Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

The research focuses on the role of microsomal prostaglandin E-synthase-1 (mPGES-1) in controlling inflammation in horses. The research found that inhibiting this enzyme selectively suppresses production of prostaglandin E (PGE), potentially providing a safer treatment for equine inflammatory disease than current non-steroidal anti-inflammatory drugs.

Objectives and Methods

  • The researchers aim to decide if mPGES-1 can be a potential target for selectively targeting PGE2, thereby effectively treating inflammatory diseases in horses in a more targeted manner. They hypothesize that mPGES-1, an enzyme down the COX-2 cascade in PGE synthesis, specifically inhibits PGE production.
  • This involves experiments conducted in leukocyte-rich plasma (LRP) obtained from whole blood samples of healthy adult horses of varying breeds and genders. The researchers used this LRP to study the effects of mPGES-1 inhibition.
  • The researchers exposed the LRP to various substances, including the mPGES-1 inhibitor MF63, a COX-2 inhibitor called NS-398, or a nonselective COX inhibitor, indomethacin. They also boosted the LRP with GM-CSF and stimulated with LPS.
  • After treating the LRP, the researchers quantified mPGES-1 and COX-2 mRNA and protein expression levels using qPCR and western blotting, respectively. They also measured concentrations of PGE, TXA, and PGI in cellular supernatants using ELISA.

Main Findings

  • LPS stimulation significantly increased mPGES-1 mRNA levels, but not protein concentration, in equine LRP.
  • Equine LRP showed a significant increase in both mRNA and protein levels of COX-2 after LPS stimulation.
  • When the researchers treated the LPS-stimulated leukocytes with either indomethacin or NS-398, it led to a reduction in the extracellular levels of multiple prostanoids. However, when they treated the cells with mPGES-1 inhibitor MF63, it only halted the production of PGE, exhibiting selective inhibition characteristics.
  • The mPGES-1 inhibitor also preserved higher basal levels of PGE production as compared to either COX inhibitor. This is considered advantageous in a clinical setting.

Conclusion

  • The study identified mPGES-1 as a crucial regulator of PGE production and as a potential selective target in equine leukocytes.
  • This highlights mPGES-1 as a potentially safer and effective treatment target for equine inflammatory diseases in comparison to traditionally used non-steroidal anti-inflammatory drugs.

Cite This Article

APA
Martin EM, Jones SL. (2017). Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE2 in an in vitro equine inflammation model. Vet Immunol Immunopathol, 192, 33-40. https://doi.org/10.1016/j.vetimm.2017.09.008

Publication

Veterinary immunology and immunopathology
ISSN: 1873-2534
NlmUniqueID: 8002006
Country: Netherlands
Language: English
Volume: 192
Pages: 33-40

Researcher Affiliations

Martin, Emily M
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.
Jones, Samuel L
  • Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA; Comparative Medicine Institute, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA. Electronic address: sam_jones@ncsu.edu.

MeSH Terms

  • Animals
  • Blotting, Western / veterinary
  • Dinoprostone / antagonists & inhibitors
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay / veterinary
  • Horses
  • Inflammation / metabolism
  • Inflammation / physiopathology
  • Inflammation / veterinary
  • Leukocytes / metabolism
  • Microsomes / enzymology
  • Prostaglandin-E Synthases / antagonists & inhibitors
  • Prostaglandin-E Synthases / metabolism
  • Prostaglandin-E Synthases / physiology
  • Real-Time Polymerase Chain Reaction / veterinary

Grant Funding

  • T35 OD011070 / NIH HHS

Conflict of Interest Statement

Conflicts of interest disclosure. The authors declare no conflict of interest.

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Citations

This article has been cited 5 times.
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