The prostaglandin EP4 receptor is a master regulator of the expression of PGE2 receptors following inflammatory activation in human monocytic cells

Alaa Kashmiry, Rothwelle Tate, Giuliana Rotondo, Jillian Davidson, Dino Rotondo

Research output: Contribution to journalArticle

Abstract

Prostaglandin E2 (PGE2) is responsible for inflammatory symptoms. However, PGE2 also suppresses pro-inflammatory cytokine production. There are at least 4 subtypes of PGE2 receptors, EP1 – EP4, but it is unclear which of these specifically control cytokine production. The aim of this study was to determine which of the different receptors, EP1R - EP4R modulate production of tumor necrosis factor-α (TNF-α) in human monocytic cells.
Human blood, or the human monocytic cell line THP-1 were stimulated with LPS. The actions of PGE2, alongside both selective agonists of EP1 – EP4 receptors, were assessed on LPS-induced TNF-α release. The expression profiles of EP2R and EP4R in monocytes and THP-1 cells were characterised by RT-qPCR. In addition, the production of TNF-α protein was evaluated following knockdown of the receptors using siRNA and over-expression of the receptors by transfection with constructs.
PGE2 and also EP2 and EP4 agonists (but not EP1 or EP3 agonists) suppressed TNF-α production in blood and THP-1 cells. LPS also up regulate expression of EP2R and EP4R but not EP1 or EP3. siRNA for either EP2R or EP4R reversed the suppressive actions of PGE2 on cytokine production and overexpression of EP2R and EP4R enhanced the suppressive actions of PGE2.
This indicates that PGE2 suppression of TNF-α by human monocytic cells occurs via EP2R and EP4R expression. However EP4Rs also control their own expression and that of EP2 whereas the EP2R does not affect EP4R expression. This implies that EP4 receptors have an important master role in controlling inflammatory responses
LanguageEnglish
Number of pages36
JournalBiochimica et Biophysica Acta Molecular and Cell Biology of Lipids
Early online date24 Jul 2018
DOIs
Publication statusE-pub ahead of print - 24 Jul 2018

Fingerprint

Receptors, Prostaglandin E, EP4 Subtype
Prostaglandin Receptors
Dinoprostone
Tumor Necrosis Factor-alpha
Cytokines
Small Interfering RNA
Receptors, Prostaglandin E, EP1 Subtype
Transfection
Monocytes
Up-Regulation
Cell Line

Keywords

  • prostaglandinEP4 receptor
  • inflammatory activation
  • human monocytic cells
  • tumor necrosis factor

Cite this

@article{6f2ba11721e74e578e198e43b2004037,
title = "The prostaglandin EP4 receptor is a master regulator of the expression of PGE2 receptors following inflammatory activation in human monocytic cells",
abstract = "Prostaglandin E2 (PGE2) is responsible for inflammatory symptoms. However, PGE2 also suppresses pro-inflammatory cytokine production. There are at least 4 subtypes of PGE2 receptors, EP1 – EP4, but it is unclear which of these specifically control cytokine production. The aim of this study was to determine which of the different receptors, EP1R - EP4R modulate production of tumor necrosis factor-α (TNF-α) in human monocytic cells.Human blood, or the human monocytic cell line THP-1 were stimulated with LPS. The actions of PGE2, alongside both selective agonists of EP1 – EP4 receptors, were assessed on LPS-induced TNF-α release. The expression profiles of EP2R and EP4R in monocytes and THP-1 cells were characterised by RT-qPCR. In addition, the production of TNF-α protein was evaluated following knockdown of the receptors using siRNA and over-expression of the receptors by transfection with constructs.PGE2 and also EP2 and EP4 agonists (but not EP1 or EP3 agonists) suppressed TNF-α production in blood and THP-1 cells. LPS also up regulate expression of EP2R and EP4R but not EP1 or EP3. siRNA for either EP2R or EP4R reversed the suppressive actions of PGE2 on cytokine production and overexpression of EP2R and EP4R enhanced the suppressive actions of PGE2.This indicates that PGE2 suppression of TNF-α by human monocytic cells occurs via EP2R and EP4R expression. However EP4Rs also control their own expression and that of EP2 whereas the EP2R does not affect EP4R expression. This implies that EP4 receptors have an important master role in controlling inflammatory responses",
keywords = "prostaglandinEP4 receptor, inflammatory activation, human monocytic cells, tumor necrosis factor",
author = "Alaa Kashmiry and Rothwelle Tate and Giuliana Rotondo and Jillian Davidson and Dino Rotondo",
year = "2018",
month = "7",
day = "24",
doi = "10.1016/j.bbalip.2018.07.003",
language = "English",
journal = "Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids",
issn = "1388-1981",

}

TY - JOUR

T1 - The prostaglandin EP4 receptor is a master regulator of the expression of PGE2 receptors following inflammatory activation in human monocytic cells

AU - Kashmiry, Alaa

AU - Tate, Rothwelle

AU - Rotondo, Giuliana

AU - Davidson, Jillian

AU - Rotondo, Dino

PY - 2018/7/24

Y1 - 2018/7/24

N2 - Prostaglandin E2 (PGE2) is responsible for inflammatory symptoms. However, PGE2 also suppresses pro-inflammatory cytokine production. There are at least 4 subtypes of PGE2 receptors, EP1 – EP4, but it is unclear which of these specifically control cytokine production. The aim of this study was to determine which of the different receptors, EP1R - EP4R modulate production of tumor necrosis factor-α (TNF-α) in human monocytic cells.Human blood, or the human monocytic cell line THP-1 were stimulated with LPS. The actions of PGE2, alongside both selective agonists of EP1 – EP4 receptors, were assessed on LPS-induced TNF-α release. The expression profiles of EP2R and EP4R in monocytes and THP-1 cells were characterised by RT-qPCR. In addition, the production of TNF-α protein was evaluated following knockdown of the receptors using siRNA and over-expression of the receptors by transfection with constructs.PGE2 and also EP2 and EP4 agonists (but not EP1 or EP3 agonists) suppressed TNF-α production in blood and THP-1 cells. LPS also up regulate expression of EP2R and EP4R but not EP1 or EP3. siRNA for either EP2R or EP4R reversed the suppressive actions of PGE2 on cytokine production and overexpression of EP2R and EP4R enhanced the suppressive actions of PGE2.This indicates that PGE2 suppression of TNF-α by human monocytic cells occurs via EP2R and EP4R expression. However EP4Rs also control their own expression and that of EP2 whereas the EP2R does not affect EP4R expression. This implies that EP4 receptors have an important master role in controlling inflammatory responses

AB - Prostaglandin E2 (PGE2) is responsible for inflammatory symptoms. However, PGE2 also suppresses pro-inflammatory cytokine production. There are at least 4 subtypes of PGE2 receptors, EP1 – EP4, but it is unclear which of these specifically control cytokine production. The aim of this study was to determine which of the different receptors, EP1R - EP4R modulate production of tumor necrosis factor-α (TNF-α) in human monocytic cells.Human blood, or the human monocytic cell line THP-1 were stimulated with LPS. The actions of PGE2, alongside both selective agonists of EP1 – EP4 receptors, were assessed on LPS-induced TNF-α release. The expression profiles of EP2R and EP4R in monocytes and THP-1 cells were characterised by RT-qPCR. In addition, the production of TNF-α protein was evaluated following knockdown of the receptors using siRNA and over-expression of the receptors by transfection with constructs.PGE2 and also EP2 and EP4 agonists (but not EP1 or EP3 agonists) suppressed TNF-α production in blood and THP-1 cells. LPS also up regulate expression of EP2R and EP4R but not EP1 or EP3. siRNA for either EP2R or EP4R reversed the suppressive actions of PGE2 on cytokine production and overexpression of EP2R and EP4R enhanced the suppressive actions of PGE2.This indicates that PGE2 suppression of TNF-α by human monocytic cells occurs via EP2R and EP4R expression. However EP4Rs also control their own expression and that of EP2 whereas the EP2R does not affect EP4R expression. This implies that EP4 receptors have an important master role in controlling inflammatory responses

KW - prostaglandinEP4 receptor

KW - inflammatory activation

KW - human monocytic cells

KW - tumor necrosis factor

U2 - 10.1016/j.bbalip.2018.07.003

DO - 10.1016/j.bbalip.2018.07.003

M3 - Article

JO - Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids

T2 - Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids

JF - Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids

SN - 1388-1981

ER -