IgE-activated human lung mast cells preferentially release prostaglandin D₂, thromboxane A₂, and cysteinyl-leukotrienes.

Abstract

The capacity of human lung mast cells (HLMC) to biosynthesize lipid mediators other than prostaglandin D₂ (PGD₂) and the cysteinyl leukotrienes is not established. We therefore profiled lipid mediator metabolites in IgE-activated HLMC. A liquid chromatography-tandem mass spectrometry platform including 107 metabolites of main endogenous polyunsaturated fatty acids was applied to supernatants of HLMC and for comparison on material from in vitro-developed cord blood mast cells. Involved pathways were defined by the use of specific pharmacologic inhibitors and transcriptomic analysis of the expression of relevant enzymes. IgE activation of HLMC profoundly increased the release of leukotriene C₄ (>500 times), PGD₂ (>200 times), and thromboxane B₂ (>100 times). In contrast, only minimal production of prostaglandin E₂, leukotriene B₄, or lipoxin A₄ was detected. The majority of the quantified compounds (n = 50) were metabolites of arachidonic acid, whereas levels of metabolites from other polyunsaturated fatty acids were low. Despite the COX-2 transcript being the most abundant species, all prostanoids, as well as lipoxin A₄ and 15-HETE, were solely biosynthesized in reactions catalyzed by COX-1. There was no apparent shunting between the main enzymatic pathways when COX-1 or 5-LOX were inhibited. Similar results were obtained in the cord blood mast cell model. There is a high degree of specialization in HLMC with a strong and specific increase in cysteinyl leukotrienes and PGD₂ but also the bronchoconstrictor thromboxane A₂ after IgE-dependent activation.