FREE SHIPPING over $40
OVER 9000 FIVE-STAR REVIEWS
5% OFF ALL SUBSCRIPTIONS
100% HAPPINESS GUARANTEE
Analyze Diet
0
Home / Equine Research Bank / Vet Immunol Immunopathol / Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1...
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.
Get Full Text
Publication Date: 2017-10-03 PubMed ID: 29042013PubMed Central: PMC6038704DOI: 10.1016/j.vetimm.2017.09.008Google Scholar: Lookup
The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
LinkedInCopy
  • Journal Article

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.

References

This article includes 22 references
  1. Bertone AL, Palmer JL, Jones J. Synovial fluid cytokines and eicosanoids as markers of joint disease in horses.. Vet Surg 2001;30:528–538.
    doi: 10.1053/jvet.2001.28430pubmed: 11704948google scholar: lookup
  2. Boulet L, Ouellet M, Bateman KP, Ethier D, Percival MD, Riendeau D, Mancini JA, Methot N. Deletion of microsomal prostaglandin E2 (PGE2) synthase-1 reduces inducible and basal PGE2 production and alters the gastric prostanoid profile.. J Biol Chem 2004;279:23229–23237.
    doi: 10.1074/jbc.M400443200pubmed: 15016822google scholar: lookup
  3. Brideau C, Van Staden C, Chan CC. In vitro effects of cyclooxygenase inhibitors in whole blood of horses, dogs, and cats.. Am J Vet Res 2001;62:1755–1760.
    pubmed: 11703020
  4. Cheng Y. Cyclooxygenases, microsomal prostaglandin E synthase-1, and cardiovascular function.. J Clin Invest 2006;116:1391–1399.
    doi: 10.1172/JCI27540pmc: PMC1435722pubmed: 16614756google scholar: lookup
  5. Cook VL, Blikslager AT. The use of nonsteroidal anti-inflammatory drugs in critically ill horses.. J Vet Emerg Crit Care 2014;25:76–88.
    doi: 10.1111/vec.12271pubmed: 25521286google scholar: lookup
  6. Cote B, Boulet L, Brideau C, Claveau D, Ethier D, Frenette R, Gagnon M, Giroux A, Guay J, Guiral S, Mancini J, Martins E, Masse F, Methot N, Riendeau D, Rubin J, Xu D, Yu H, Ducharme Y, Friesen RW. Substituted phenanthrene imidazoles as potent, selective, and orally active mPGES-1 inhibitors.. Bioorg Med Chem Lett 2007;17:6816–6820.
    pubmed: 18029174
  7. Eckert RE, Neuder LE, Bell JL, Trujillo JC, Jones SL. The role of p38 mitogen-activated kinase (MAPK) in the mechanism regulating cyclooxygenase gene expression in equine leukocytes.. Vet Immunol Immunopathol 2007;118:294–303.
    doi: 10.1016/j.vetimm.2007.06.001pubmed: 17614138google scholar: lookup
  8. Koeberle A, Werz O. Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders.. Biochem Pharmacol 2015;98:1–15.
    pubmed: 26123522
  9. Li X, Afif H, Cheng S, Martel-Pelletier J, Pelletier JP, Ranger P, Fahmi H. Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes.. J Rheumatol 2005;32:887–895.
    pubmed: 15868626
  10. Marshall JF, Blikslager AT. The effect of nonsteroidal anti-inflammatory drugs on the equine intestine.. Equine Vet J 2011;43:140–144.
    doi: 10.1111/j.2042-3306.2011.00398.xpubmed: 21790769google scholar: lookup
  11. Morgan MJ, Liu Z-G. Crosstalk of Reactive Oxygen Species and NF-κB Signaling 21.. Nature Publishing Group; 2010. pp. 103–115.
    doi: 10.1038/cr.2010.178pmc: PMC3193400pubmed: 21187859google scholar: lookup
  12. Mosca M, Polentarutti N, Mangano G, Apicella C, Doni A, Mancini F, De Bortoli M, Coletta I, Polenzani L, Santoni G, Sironi M, Vecchi A, Mantovani A. Regulation of the microsomal prostaglandin E synthase-1 in polarized mononuclear phagocytes and its constitutive expression in neutrophils.. J Leukoc Biol 2007;82:320–326.
    doi: 10.1189/jlb.0906576pubmed: 17505022google scholar: lookup
  13. Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T, Fueki M, Ueno A, Oh-ishi S, Kudo I. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2.. J Biol Chem 2000;275:32783–32792.
    doi: 10.1074/jbc.M003505200pubmed: 10869354google scholar: lookup
  14. Murakami M, Nakashima K, Kamei D, Masuda S, Ishikawa Y, Ishii T, Ohmiya Y, Watanabe K, Kudo I. Cellular prostaglandin E2 production by membrane-bound prostaglandin e synthase-2 via both cyclooxygenases-1 and -2.. J Biol Chem 2003;278:37937–37947.
    doi: 10.1074/jbc.M305108200pubmed: 12835322google scholar: lookup
  15. Prisk V, Huard J. Muscle injuries and repair: the role of prostaglandins and inflammation.. Histol Histopathol 2003;18:1243–1256.
    pubmed: 12973691
  16. Radonić A, Thulke S, Mackay IM, Landt O, Siegert W, Nitsche A. Guideline to reference gene selection for quantitative real-time PCR.. Biochem Biophys Res Commun 2004;313:856–862.
    doi: 10.1016/j.bbrc.2003.11.177pubmed: 14706621google scholar: lookup
  17. Salazar F, Vazquez ML, Mansferrer JL, Mbalaviele G, Llinas MT, Saez F, Arhancet G, Salazar FJ. Renal effects induced by prolonged mPGES1 inhibition.. Am J Physiol Renal Physiol 2014;306:F68–F74.
    pubmed: 24197070
  18. Sharma JN, Jawad NM. Adverse effects of COX-2 inhibitors.. Sci World J 2005;5:629–645.
    doi: 10.1100/tsw.2005.82pmc: PMC5936602pubmed: 16113940google scholar: lookup
  19. St-Onge M, Flamand N, Biarc J, Picard S, Bouchard L, Dussault AA, Laflamme C, James MJ, Caughey GE, Cleland LG, Borgeat P, Pouliot M. Characterization of prostaglandin E2 generation through the cyclooxygenase (COX)-2 pathway in human neutrophils.. Biochim Biophys Acta (BBA) Mol Cell Biol Lipids 2007;1771:1235–1245.
    doi: 10.1016/j.bbalip.2007.06.002pmc: PMC2891965pubmed: 17643350google scholar: lookup
  20. Tanioka T, Nakatani Y, Semmyo N, Murakami M, Kudo I. Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2Biosynthesis.. J Biol Chem 2000;275:32775–32782.
    doi: 10.1074/jbc.M003504200pubmed: 10922363google scholar: lookup
  21. Trebino CE, Stock JL, Gibbons CP, Naiman BM, Wachtmann TS, Umland JP, Pandher K, Lapointe JM, Saha S, Roach ML, Carter D, Thomas NA, Durtschi BA, McNeish JD, Hambor JE, Jakobsson PJ, Carty TJ, Perez JR, Audoly LP. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase.. Proc Natl Acad Sci U S A 2003;100:9044–9049.
    pmc: PMC166435pubmed: 12835414
  22. Xu D, Rowland SE, Clark P, Giroux A, Cote B, Guiral S, Salem M, Ducharme Y, Friesen RW, Methot N, Mancini J, Audoly L, Riendeau D. MF63 [2-(6-Chloro-1H-phenanthro[9, 10-d]imidazol-2-yl)-isophthalonitrile], a selective microsomal prostaglandin e synthase-1 inhibitor, relieves pyresis and pain in preclinical models of inflammation.. J Pharmacol Exp Ther 2008;326:754–763.
    doi: 10.1124/jpet.108.138776pubmed: 18524979google scholar: lookup

Citations

This article has been cited 5 times.
  1. Alqarni AA, Aldhahir AM, Alghamdi SA, Alqahtani JS, Siraj RA, Alwafi H, AlGarni AA, Majrshi MS, Alshehri SM, Pang L. Role of prostanoids, nitric oxide and endothelin pathways in pulmonary hypertension due to COPD. Front Med (Lausanne) 2023;10:1275684.
    doi: 10.3389/fmed.2023.1275684pubmed: 37881627google scholar: lookup
  2. LaBorde K, Lu R, Ruan KH. Latest progress in the development of cyclooxygenase-2 pathway inhibitors targeting microsomal prostaglandin E(2) synthase-1. Future Med Chem 2022 Mar;14(6):385-388.
    doi: 10.4155/fmc-2021-0317pubmed: 34985304google scholar: lookup
  3. Luo Q, Hu Q, Zheng Q, Gong L, Su L, Ren B, Ju Y, Jia Z, Dou X. Enhanced mPGES-1 Contributes to PD-Related Peritoneal Fibrosis via Activation of the NLRP3 Inflammasome. Front Med (Lausanne) 2021;8:675363.
    doi: 10.3389/fmed.2021.675363pubmed: 34084773google scholar: lookup
  4. Rappl P, Rösser S, Maul P, Bauer R, Huard A, Schreiber Y, Thomas D, Geisslinger G, Jakobsson PJ, Weigert A, Brüne B, Schmid T. Inhibition of mPGES-1 attenuates efficient resolution of acute inflammation by enhancing CX3CL1 expression. Cell Death Dis 2021 Feb 2;12(2):135.
    doi: 10.1038/s41419-021-03423-2pubmed: 33542207google scholar: lookup
  5. Wang Q, Li Y, Wu M, Huang S, Zhang A, Zhang Y, Jia Z. Targeting microsomal prostaglandin E synthase 1 to develop drugs treating the inflammatory diseases. Am J Transl Res 2021;13(1):391-419.
    pubmed: 33527033
Subscribe to our newsletter
Join 99,357 horse owners like you who receive our email updates on horse health and nutrition.