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

Kashmiry, Alaa and Tate, Rothwelle and Rotondo, Giuliana and Davidson, Jillian and Rotondo, Dino (2018) The prostaglandin EP4 receptor is a master regulator of the expression of PGE2 receptors following inflammatory activation in human monocytic cells. Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, 1863 (10). pp. 1297-1304. ISSN 1388-1981 (https://doi.org/10.1016/j.bbalip.2018.07.003)

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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

ORCID iDs

Kashmiry, Alaa, Tate, Rothwelle, Rotondo, Giuliana, Davidson, Jillian and Rotondo, Dino ORCID logoORCID: https://orcid.org/0000-0002-9008-4329;
CORE (COnnecting REpositories)