Low IL-13R & alpha;1 expression on mast cells tunes them unresponsive to IL-13

Cytokine-mediated mast cell regulation enables precise optimization of their own proinflammatory cytokine production. During allergic inflammation, interleukin (IL)-4 regulates mast cell functions, tissue homing, and proliferation, but the direct role of closely related IL-13 for mast cell activation remains unclear. Previous work has shown that mast cells are potent IL-13 producers, but here we show that mouse mast cells do not directly respond to IL-13 by Stat6 activation, as they do not express measurable amount of IL-13 receptor & alpha;1 (IL-4R & alpha;1) messenger RNA. Consequently, IL-4 responses are mediated via type I IL-4R (IL-4/IL4R & alpha;/& gamma;C), and IL-4-induced Stat6 activation is abolished in & gamma;C-deficient mast cells. Type II IL-4R deficiency (IL-13R & alpha;1 knockout) has no effect on IL-4-induced Stat6 activation. In basophils, both IL-4 and IL-13 induce Stat6 activation in wild-type and & gamma;C-deficient cells, while in type II IL-4R-deficient basophils, IL-4 signaling is impaired at low ligand concentration. Thus, mast cell and basophil sensitivity to IL-4/IL-13 is different, and in mast cells, lack of IL-13R & alpha;1 expression likely explains their unresponsiveness to IL-13. Mast cells and basophils are effector cells of type2 inflammation. Here, their responsiveness to hallmark type II cytokine interleukin (IL)-13 is shown to be completely different. This suggests that neutralizing IL-13 or IL-13 receptor & alpha;1 has no direct functional consequences related to mast cell activation, while in closely related basophils this would be efficient. In short, mast cell and basophil responsiveness to IL-13 is completely different.