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

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• 作者：Liliana Machado-Carvalho ; MS^a ; ^b ; ^{lsmachad@clinic.ub.es" class="auth_mail" title="E-mail the corresponding author} ; Margarita Martí ; n ; PhD^a ; ^c ; Rosa Torres ; PhD^a ; ^b ; ^d ; Marta Gabasa ; PhD^a ; ^b ; Isam Alobid ; MD ; PhD^a ; ^b ; ^e ; Joaquim Mullol ; MD ; PhD^a ; ^b ; ^e ; Laura Pujols ; PhD^a ; ^b ; Jordi Roca-Ferrer ; PhD^a ; ^b ; ^&lowast ; ; Cesar Picado ; MD ; FERS ; PhD^a ; ^b ; ^f ; ^&lowast ;
• 关键词：Aspirin-exacerbated respiratory disease ; COX-2 ; E-prostanoid 2 receptor ; fibroblasts ; IL-1β ; IL-1 receptor type I ; microsomal prostaglandin E synthase 1 ; nasal mucosa ; nasal polyps ; prostaglandin E2
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：137
• 期：1
• 页码：99-107.e7
• 全文大小：2130 K

文摘

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.

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 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.

Results

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.

Conclusion

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.