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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Machado-Carvalho, Liliana^1,2  Martin, Margarita^1,3  Torres, Rosa^1,2,5  Gabasa, Marta^1,2  Alobid, Isam^1,2,6,7  Mullol, Joaquim^1,2,6,7  Pujols, Laura^1,2  Roca-Ferrer, Jordi^1,2  Picado, Cesar^1,2,4 

[1] IDIBAPS, Clin & Expt Resp Immunoallergy, Barcelona 08036, Spain

[2] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Resp CIBERES, Madrid, Spain

[3] Univ Barcelona, Sch Med, Biochem Unit, E-08007 Barcelona, Spain

[4] Univ Barcelona, Hosp Clin, Pneumol & Resp Allergy Dept, E-08007 Barcelona, Spain

[5] Univ Autonoma Barcelona, Dept Pharmacol, E-08193 Barcelona, Spain

[6] Hosp Clin Barcelona, Rhinol Unit, Barcelona, Spain

[7] Hosp Clin Barcelona, ENT Dept, Smell Clin, Barcelona, Spain

关键词: Aspirin-exacerbated respiratory disease;    COX-2;    E-prostanoid 2 receptor;    fibroblasts;    IL-1 beta;    IL-1 receptor type I;    microsomal prostaglandin E synthase 1;    nasal mucosa;    nasal polyps;    prostaglandin E-2;   

DOI  :  10.1016/j.jaci.2015.09.028

来源: Elsevier

【 摘 要 】

Background: We hypothesized that the 2 reported alterations in aspirin-exacerbated respiratory disease (AERD), reduced expression/production of COX-2/prostaglandin (PG) E-2 and diminished expression of E-prostanoid (EP) 2 receptor, are closely linked. Objective: We sought to determine the mechanisms involved in the altered regulation of the COX pathway in patients with AERD. Methods: 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 PGE(2) 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-1 beta, PGE(2), and specific EP receptor agonists. Results: Compared with NM-C fibroblasts, basal expression levels of IL-1RI and EP2 receptor were lower in NP-AERD fibroblasts. IL-1 beta-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 PGE(2) 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. Conclusion: Altered expression of EP2 in patients with AERD contributes to deficient induction of IL-1RI, reducing the capacity of IL-1 beta to increase COX-2 and mPGES-1 expression, which results in low PGE(2) production. This impairment in the generation of PGE(2) subsequently reduces its ability to induce IL-1RI.

【 授权许可】

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