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Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE2 in an in vitro equine inflammation model.
Vet Immunol Immunopathol. 2017 Oct; 192:33-40.VI

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.

Authors+Show Affiliations

Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29042013

Citation

Martin, Emily M., and Samuel L. Jones. "Inhibition of Microsomal Prostaglandin E-synthase-1 (mPGES-1) Selectively Suppresses PGE2 in an in Vitro Equine Inflammation Model." Veterinary Immunology and Immunopathology, vol. 192, 2017, pp. 33-40.
Martin EM, Jones SL. Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE2 in an in vitro equine inflammation model. Vet Immunol Immunopathol. 2017;192:33-40.
Martin, E. M., & Jones, S. L. (2017). Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE2 in an in vitro equine inflammation model. Veterinary Immunology and Immunopathology, 192, 33-40. https://doi.org/10.1016/j.vetimm.2017.09.008
Martin EM, Jones SL. Inhibition of Microsomal Prostaglandin E-synthase-1 (mPGES-1) Selectively Suppresses PGE2 in an in Vitro Equine Inflammation Model. Vet Immunol Immunopathol. 2017;192:33-40. PubMed PMID: 29042013.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of microsomal prostaglandin E-synthase-1 (mPGES-1) selectively suppresses PGE2 in an in vitro equine inflammation model. AU - Martin,Emily M, AU - Jones,Samuel L, Y1 - 2017/10/03/ PY - 2017/03/29/received PY - 2017/09/13/revised PY - 2017/09/30/accepted PY - 2017/10/19/entrez PY - 2017/10/19/pubmed PY - 2018/4/18/medline KW - Anti-inflammatory KW - Horse KW - Leukocyte KW - NSAID KW - Prostaglandin E(2) KW - Prostaglandin E-synthase SP - 33 EP - 40 JF - Veterinary immunology and immunopathology JO - Vet. Immunol. Immunopathol. VL - 192 N2 - 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. SN - 1873-2534 UR - https://www.unboundmedicine.com/medline/citation/29042013/Inhibition_of_microsomal_prostaglandin_E_synthase_1__mPGES_1__selectively_suppresses_PGE2_in_an_in_vitro_equine_inflammation_model_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0165-2427(17)30159-9 DB - PRIME DP - Unbound Medicine ER -