Prominent role of IFN-γ in patients with aspirin-exacerbated respiratory disease

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:132

Article

Steinke, John W.^1,2  Liu, Lixia¹  Huyett, Phillip¹  Negri, Julie¹  Payne, Spencer C.^1,3  Borish, Larry^1,2 

[1] Univ Virginia Hlth Syst, Asthma & Allerg Dis Ctr, Charlottesville, VA 22903 USA

[2] Univ Virginia Hlth Syst, Carter Immunol Ctr, Charlottesville, VA USA

[3] Univ Virginia Hlth Syst, Dept Otolaryngol Head & Neck Surg, Charlottesville, VA USA

关键词: Aspirin-exacerbated respiratory disease;    aspirin-tolerant asthma;    chronic sinusitis;    cytokines;    eosinophils;    IFN-gamma;    nasal polyps;   

DOI  :  10.1016/j.jaci.2013.05.008

来源: Elsevier

【 摘 要 】

Background: Aspirin-exacerbated respiratory disease (AERD) is distinguished from aspirin-tolerant asthma/chronic sinusitis in large part by an exuberant infiltration of eosinophils that are characterized by their overexpression of metabolic pathways that drive the constitutive and aspirin-induced secretion of cysteinyl leukotrienes (CysLTs). Objective: We defined the inflammatory milieu that in part drives CysLT overproduction and, in particular, the role of IFN-gamma in the differentiation of eosinophils. Methods: Quantitative real-time PCR was performed for T(H)1 and T(H)2 signature cytokines on tissue from control subjects, patients with chronic hyperplastic eosinophilic sinusitis, and patients with AERD, and their cellular source was determined. The influence of IFN-gamma on maturation, differentiation, and functionality of eosinophils derived from hematopoietic stem cells was determined. Results: Gene expression analysis revealed that tissue from both aspirin-tolerant subjects and patients with AERD display a TH2 cytokine signature; however, AERD was distinguished from chronic hyperplastic eosinophilic sinusitis by the prominent expression of IFN-gamma. Intracellular and immunohistochemical cytokine staining revealed that the major sources of these cytokines were the eosinophils themselves. IFN-gamma promoted the maturation of eosinophil progenitors, as measured by increased mRNA and surface expression of CCR3 and sialic acid-binding immunoglobulin-like lectin 8 (Siglec-8). Additionally, IFN-gamma increased the expression of genes involved in leukotriene synthesis that led to increased secretion of CysLTs. IFN-gamma-matured eosinophil progenitors were also primed, as demonstrated by their enhanced degranulation. Conclusions: High IFN-gamma levels distinguish AERD from aspirin-tolerant asthma and underlie the robust constitutive and aspirin-induced secretion of CysLTs that characterize this disorder.

【 授权许可】

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