Prostaglandin E₂ suppresses staphylococcal enterotoxin–induced eosinophilia-associated cellular responses dominantly through an E-prostanoid 2–mediated pathway in nasal polyps

Background

Recent investigations have revealed that staphylococcal enterotoxins (SEs), COX metabolism, or both might participate in the pathogenesis of eosinophilic airway diseases, such as chronic rhinosinusitis with nasal polyposis.

Objective

We sought to determine whether COX metabolism, especially prostaglandin (PG) E₂, plays a significant role in SE-induced cellular responses in nasal polyps.

Methods

Dispersed nasal polyp cells (DNPCs) were prepared from nasal polyps by means of enzymatic digestion. DNPCs were cultured with SEB in the presence or absence of COX inhibitors (diclofenac and indomethacin) for 72 hours; then the levels of IL-5, IL-13, RANTES, and eotaxin in the supernatants were measured. The effect of PGE₂ on SEB-induced responses by diclofenac-treated DNPCs was examined, especially in terms of receptor specificity.

Results

DNPCs produced significant amounts of IL-5, IL-13, and RANTES in response to SEB. COX inhibitors significantly increased the production of these cytokines. The degree of local eosinophilia was significantly and positively correlated with the changes in IL-5 production induced by diclofenac treatment. PGE₂ significantly and dose-dependently inhibited SEB-induced IL-5, IL-13, and RANTES production by diclofenac-treated DNPCs. E-prostanoid (EP) 2 receptor–selective agonist strongly inhibited the production of all 3 cytokines. EP3 and EP4 receptor–selective agonists partially suppressed these responses, whereas EP1 receptor–selective agonist did not. Interestingly, all of the combined treatments with 2 of the 4 EP receptor–selective agonists significantly inhibited the SEB-induced responses by diclofenac-treated DNPCs.

Conclusions

These results suggest that PGE₂ inhibits the pathogenesis of SEB-induced eosinophilic inflammation primarily through the EP2-mediated pathway in patients with chronic rhinosinusitis with nasal polyposis.

Key words: Enterotoxin, COX, prostaglandin E₂, E-prostanoid receptor, IL-5, IL-13, RANTES, nasal polyps, chronic rhinosinusitis

Abbreviations used: CRS-NP, Chronic rhinosinusitis with nasal polyposis, DMSO, Dimethyl sulfoxide, DNPC, Dispersed nasal polyp cell, ECP, Eosinophil cationic protein, EP, E-prostanoid, ICAM-1, Intercellular adhesion molecule 1, m-PGES-1, Microsomal PGE₂ synthase 1, NSAID, Nonsteroidal anti-inflammatory drug, PG, Prostaglandin, SE, Staphylococcal enterotoxin