Low E-prostanoid 2 receptor levels and deficient induction of the IL-1β/IL-1 type I receptor/COX-2 pathway: Vicious circle in patients with aspirin-exacerbated respiratory disease

• Published in: Journal of allergy and clinical immunology Vol. 137; no. 1; pp. 99 - 107.e7
• Main Authors: Machado-Carvalho, Liliana, Martín, Margarita, Torres, Rosa, Gabasa, Marta, Alobid, Isam, Mullol, Joaquim, Pujols, Laura, Roca-Ferrer, Jordi, Picado, Cesar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2016
• Subjects: Adult; Aged; Allergy and Immunology; Alprostadil - analogs & derivatives; Alprostadil - pharmacology; Aspirin - pharmacology; Aspirin-exacerbated respiratory disease; Asthma, Aspirin-Induced - metabolism; Cells, Cultured; COX-2; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Dinoprostone - pharmacology; E-prostanoid 2 receptor; Female; fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; IL-1 receptor type I; IL-1β; Interleukin-1beta - metabolism; Intramolecular Oxidoreductases - metabolism; Male; microsomal prostaglandin E synthase 1; Middle Aged; nasal mucosa; Nasal Mucosa - cytology; nasal polyps; Nasal Polyps - metabolism; prostaglandin E2; Prostaglandin-E Synthases; Receptors, Interleukin-1 Type I - genetics; Receptors, Interleukin-1 Type I - metabolism; Receptors, Prostaglandin E, EP2 Subtype - agonists; Receptors, Prostaglandin E, EP2 Subtype - metabolism; RNA, Messenger - metabolism; microsomal prostaglandin E synthase 1; NP-AERD; COX-2; Aspirin-exacerbated respiratory disease; NSAID; AERD; cAMP; ASA; E-prostanoid 2 receptor; GFP; DMEM; NM-C; fibroblasts; prostaglandin E2; nasal polyps; nasal mucosa; IL-1 receptor type I; SFM; AA; mPGES-1; PKA; siRNA; EP; IL-1RI; IL-1β; PG; GAPDH; Protein kinase A; Nasal mucosa of control subjects; Small interfering RNA; Nasal polyps from patients with aspirin-exacerbated respiratory disease; Acetylsalicylic acid; Arachidonic acid; E-prostanoid; Serum-free medium; Dulbecco modified Eagle medium; prostaglandin E 2; Prostaglandin; Cyclic AMP; Green fluorescent protein; Nonsteroidal anti-inflammatory drug; Glyceraldehyde-3-phosphate dehydrogenase; prostaglandin E
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2015.09.028

We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E2 and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked. We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD. Fibroblasts were obtained from nasal mucosa; samples of control subjects (NM-C, n = 8) and from nasal polyps from patients with aspirin-exacerbated respiratory disease (NP-AERD, n = 8). Expression of the autocrine loop components regulating PGE2 production and signaling, namely IL-1 type I receptor (IL-1RI), COX-2, microsomal prostaglandin E synthase 1 (mPGES-1), and EP receptors, was assessed at baseline and after stimulation with IL-1β, PGE2, and specific EP receptor agonists. Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP2 receptor were lower in NP-AERD fibroblasts. IL-1β–induced IL-1RI, COX-2, and mPGES-1 expression levels were also lower in these cells. Levels of IL-1RI positively correlated with COX-2 and mPGES-1 expression in both NM-C and NP-AERD fibroblasts. Incubation with either exogenous PGE2 or selective EP2 agonist significantly increased expression of IL-1RI in NM-C fibroblasts and had hardly any effect on NP-AERD fibroblasts. Alterations in IL-1RI, COX-2, and mPGES-1 expression that were found in NP-AERD fibroblasts were corrected when EP2 receptor expression was normalized by transfection of NP-AERD fibroblasts. Altered expression of EP2 in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1β to increase COX-2 and mPGES-1 expression, which results in low PGE2 production. This impairment in the generation of PGE2 subsequently reduces its ability to induce IL-1RI.