Σφακιανάκης Αλέξανδρος
ΩτοΡινοΛαρυγγολόγος
Αναπαύσεως 5 Άγιος Νικόλαος
Κρήτη 72100
00302841026182
00306932607174
alsfakia@gmail.com

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Πέμπτη 12 Ιουλίου 2018

Cyclooxygenase 1 mediates IL-33-induced extracellular signal regulated kinase activation in mast cells; Implications for aspirin sensitivity

Publication date: Available online 12 July 2018

Source: Journal of Allergy and Clinical Immunology

Author(s): Dingxin Pan, Kathleen M. Buchheit, Sachin K. Samuchiwal, Tao Liu, Haley Cirka, Hannah Raff, Joshua A. Boyce

Abstract
Background

Classical FcεRI-induced mast cell (MC) activation causes synthesis of arachidonic acid (AA)-derived eicosanoids (leukotriene (LT)C4, prostaglandin D2 (PGD2), and thromboxane A2 (TXA2)), that mediate vascular leak, bronchoconstriction, and effector cell chemotaxis. Little is known about the significance and regulation of eicosanoid generation in response to non-classical MC activation mechanisms.

Objectives

To determine the regulation and significance of MC-derived eicosanoids synthesized in response to interleukin-33 (IL-33), a cytokine critical to innate type 2 immunity.

Methods

We employed an ex vivo model of mouse bone marrow-derived MCs (BMMCs) and an IL-33-dependent in vivo model of aspirin-exacerbated respiratory disease.

Results

IL-33 potently liberates AA and elicits LTC4, PGD2, and TXA2 production by BMMCs. Unexpectedly, the constitutive function of cyclooxygenase (COX)-1 is required for IL-33 to activate group IVA cytosolic phospholipase A2 (cPLA2) with consequent AA release for synthesis of all eicosanoids, including cysLTs. In contrast, COX-1 was dispensable for FcεRI-driven cysLT production. Inhibition of COX-1 prevented IL-33 induced phosphorylation of extracellular signal related kinase (ERK), an upstream effector of cPLA2, which was restored by exogenous PGH2, implying that the effects of COX-1 required its catalytic function. The administration of a COX-1-selective antagonist to mice completely prevented the generations of both PGD2 and LTC4 in a model of AERD in which MC activation is IL-33-driven.

Conclusions

MC-intrinsic COX-1 amplifies IL-33-induced activation in the setting of innate type 2 immunity, and may help explain the phenomenon of therapeutic desensitization to aspirin by nonselective COX inhibitors in AERD.



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