Activation of the EP 4 prostanoid receptor induces prostaglandin E 2 and pro-inflammatory cytokine production in human airway epithelial cells

Abstract

Prostaglandin (PG)E 2 mediates its effects via activation of four distinct PGE 2 receptors, termed EP 1– 4, all of which are present on the model human airway epithelial cell line, Calu-3. We previously reported that acute activation of the EP 4 subtype of the PGE 2 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 EP 4 receptor in Calu-3 cells in an attempt to determine whether this would prove beneficial or detrimental to the airway epithelial cell environment. Using PGE 1-OH, an EP 4 receptor selective agonist, we determined that EP 4 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 PGE 2, IL-6, IL-8 and the chemokine monocyte chemotactic protein-1 (MCP-1) at both the protein and gene level in response to EP 4 receptor activation. Intriguingly, the enhanced production of PGE 2 in response to EP 4 receptor activation raises the possibility of a positive feedback situation. Generally, within the airways, PGE 2 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 EP 4 receptor is associated with increased production of mediators likely to increase the pro-inflammatory milieu of airway epithelial cells.