Leukotriene enhanced allergic lung inflammation through induction of chemokine production (HYP4P.414)

Abstract

Abstract Leukotrienes, which are mainly expressed by mast cells, macrophages and eosinophils, have been shown to act as important mediators in allergic asthma. In addition to leukotrienes, IL-13, a Th2 specific cytokine, has also been considered as the most important effector cytokine to induce allergic asthma, by increasing airway hyper-responsiveness, airway inflammation, eosinophilia and mucus hyper-production. But, the exact mechanisms how leukotrienes elicit allergic lung responses at initial stage and the effect of leukotrienes on allergic asthma through IL-13 remain unclear. To reveal this, we adopted two distinct models of allergic inflammation: intranasal Aspergillus protease allergen and recombinant IL-13 induced Th2 mediated inflammation. Here we measured AHR, bronchoalveolar lavage cytology, glycoprotein secretion, as well as IL-13 related chemokines such as CCL7, CCL11 and CCL17, which directly regulate homing of Th2 cells to lung with 5-lipoxygenase deficient and wild type mice. 5-lipoxygenase that convert arachidonic acid into leukotriene A4 null mice showed attenuated airway inflammation, AHR and bronchoalveolar lavage eosinophilia, as well as diminished chemokines including CCL7 and CCL17. Finally, addition of LTB4 and LTC4 to the airways of 5-lipoxygenase deficient mice restored rIL-13 induced asthma. Thus, our results indicate that LTs augment the effect of IL-13 in allergic asthma, are required for Th2 specific chemokine production.