Activation of the EP₄ prostanoid receptor induces prostaglandin E₂ and pro-inflammatory cytokine production in human airway epithelial cells.
Prostaglandin (PG)E₂ mediates its effects via activation of four distinct PGE₂ receptors, termed EP₁₋₄, all of which are present on the model human airway epithelial cell line, Calu-3. We previously reported that acute activation of the EP₄ subtype of the PGE₂ receptor is associated with increased anion efflux from these cells, via the CFTR chloride channel. In the present study we examine the effects of longer term activation of the EP₄ receptor in Calu-3 cells in an attempt to determine whether this would prove beneficial or detrimental to the airway epithelial cell environment. Using PGE₁-OH, an EP₄ receptor selective agonist, we determined that EP₄ receptor activation was associated with increased phosphorylation of extracellular signal-related kinases (ERKs) and induction of the transcription factor early growth response factor-1 (Egr-1). Additionally, using specific enzyme-linked immunosorbent assays and quantitative PCR, we detected increased production of PGE₂, IL-6, IL-8 and the chemokine monocyte chemotactic protein-1 (MCP-1) at both the protein and gene level in response to EP₄ receptor activation. Intriguingly, the enhanced production of PGE₂ in response to EP₄ receptor activation raises the possibility of a positive feedback situation. Generally, within the airways, PGE₂ is considered to have pro-inflammatory effects, whilst the enhanced production of IL-6, IL-8 and MCP-1 would be associated with the recruitment and activation of inflammatory cells to the airways. Thus, we conclude that chronic activation of the EP₄ receptor is associated with increased production of mediators likely to increase the pro-inflammatory milieu of airway epithelial cells.
Li
Tiesong
T
Department of Physiology and Biophysics, Dalhousie University, Halifax, Nova Scotia B3H1X5, Canada.
Qi
Jiansong
J
Cowley
Elizabeth A
EA
D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis*; D015232:Dinoprostone / Q000096:biosynthesis*; D051766:Early Growth Response Protein 1 / Q000032:analysis; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000502:physiology*; D014132:Trachea / Q000378:metabolism*
C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D015850:Interleukin-6; D016209:Interleukin-8; D058309:Receptors, Prostaglandin E, EP4 Subtype; D048049:Extracellular Signal-Regulated MAP Kinases; D015232:Dinoprostone