Premium
The anti‐inflammatory effects of PGE 2 on human lung macrophages are mediated by the EP 4 receptor
Author(s) -
Gill Sharonjit K,
Yao Yiwen,
Kay Linda J,
Bewley Martin A,
Marriott Helen M,
Peachell Peter T
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13565
Subject(s) - receptor , agonist , cytokine , prostaglandin e2 receptor , chemistry , interleukin 21 receptor , pharmacology , receptor expression , tumor necrosis factor alpha , medicine , endocrinology , biology , biochemistry
Background and Purpose PGE 2 inhibits cytokine generation from human lung macrophages. However, the EP receptor that mediates this beneficial anti‐inflammatory effect of PGE 2 has not been defined. The aim of this study was to identify the EP receptor by which PGE 2 inhibits cytokine generation from human lung macrophages. This was determined by using recently developed EP receptor ligands. Experimental Approach The effects of PGE 2 and EP‐selective agonists on LPS‐induced generation of TNF‐α and IL‐6 from macrophages were evaluated. The effects of EP 2 ‐selective (PF‐04852946, PF‐04418948) and EP 4 ‐selective (L‐161,982, CJ‐042794) receptor antagonists on PGE 2 responses were studied. The expression of EP receptor subtypes by human lung macrophages was determined by RT‐PCR. Key Results PGE 2 inhibited LPS‐induced and Streptococcus pneumoniae ‐induced cytokine generation from human lung macrophages. Analysis of mRNA levels indicated that macrophages expressed EP 2 and EP 4 receptors. L‐902,688 (EP 4 receptor‐selective agonist) was considerably more potent than butaprost (EP 2 receptor‐selective agonist) as an inhibitor of TNF‐α generation from macrophages. EP 2 receptor‐selective antagonists had marginal effects on the PGE 2 inhibition of TNF‐α generation, whereas EP 4 receptor‐selective antagonists caused rightward shifts in the PGE 2 concentration–response curves. Conclusions and Implications These studies demonstrate that the EP 4 receptor is the principal receptor that mediates the anti‐inflammatory effects of PGE 2 on human lung macrophages. This suggests that EP 4 receptor agonists could be effective anti‐inflammatory agents in human lung disease.