Interactions between leukotriene C₄ and interleukin 13 signaling pathways in a mouse model of airway disease

Context. - During an asthmatic episode, leukotriene C₄ (LTC ₄) and interleukin 13 (IL-13) are released into the airways and are thought to be central mediators of the asthmatic response. However, little is known about how these molecules interact or affect each other's signaling pathway. Objective. - To determine if the LTC₄ and IL-13 signaling pathways interact with each other's pathways. Design. - We examined airway responsiveness, cysteinyl LTs (Cys-LTs), and Cys-LT and IL-13 receptor transcript levels in wild-type mice and in mice that were deficient in γ-glutamyl leukotrienase (an enzyme that converts LTC₄ to LTD₄), STAT6 (signal transducer and activator of transcription 6 [a critical molecule in IL-13 signaling]), and IL-4Rα (a subunit of the IL-13 receptor). Results. - Wild-type (C57BL/129SvEv) and γ-glutamyl leukotnenase-deficient mice showed increased airway responsiveness after intranasal instillation of IL-13; similar results were observed after intranasal instillation of IL-13 or LTC₄ in a second wild-type strain (BALB/c). Interleukin 13 treatment reduced levels of Cys-LTs in bronchoalveolar lavage fluid. This change was unaccompanied by changes in other arachidonic acid metabolites or in RNA transcript levels of enzymes associated with Cys-LT synthesis. Interleukin 13 treatment also increased transcript levels of the Cys-LT 1 and Cys-LT 2 receptors, while LTC₄ increased transcript levels of the α1 chain of the IL-13 receptor. Furthermore, IL-4Rα-deficient mice had increased airway responsiveness to LTC ₄ but not to IL-13, whereas STAT6-deficient mice failed to respond to either agonist. Conclusions. - These findings indicate that LTC₄ and IL-13 are dependent on or signal through STAT6 to increase airway responsiveness and that both agonists regulate expression of each other's receptors.